1
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Bangbo Z, Cheng Q, Zeru L, Tianyu L, Yutong Z, Weibin W, Yupei Z. RNA binding protein Pumilio2 promotes chemoresistance of pancreatic cancer via focal adhesion pathway and interacting with transcription factor EGR1. Cell Mol Life Sci 2025; 82:78. [PMID: 39961821 PMCID: PMC11832970 DOI: 10.1007/s00018-025-05599-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/20/2025]
Abstract
Pancreatic cancer (PCa) has insidious onset, high malignancy and poor prognosis. Gemcitabine (GEM) is one of the first-line chemotherapy drugs for PCa. However, GEM resistance has always been a bottleneck problem leading to recurrence and death of PCa patients. RNA-binding proteins (RBPs) are important proteins that regulate transportation, splicing, stability and translation of RNA. Abnormal expression of RBPs often lead to a series of abnormal accumulation or degradation of downstream RNA resulting in various diseases. In our study, we utilized RIP seq, RIP-qPCR, in vitro and in vivo experiments and found that pumilio2 (PUM2) was high expression in PCa, and promoted GEM resistance of PCa by regulating mRNA stability of integrin Alpha 3 (ITGA3) and other genes in focal adhesion pathway, and there was positive feedback regulation between PUM2 and transcription factor early growth response gene 1 (EGR1), that is PUM2 binding to 3'UTR region of EGR1 mRNA, and EGR1 binding to promoter region of PUM2 gene. The discovery of EGR1/PUM2/ITGA3 axis provided a solid experimental basis for the selection of chemotherapy regiments for PCa patients and exploration of combined regimens to reverse GEM resistance in the future.
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Affiliation(s)
- Zhao Bangbo
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qin Cheng
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Li Zeru
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Li Tianyu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zhao Yutong
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Wang Weibin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Zhao Yupei
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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2
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Hu Y, Hu Y, Zhang S, Guo Y, Wang F, Du Y, Wang L, Li P, Xu Y, Zhang H, Yang Z, Liu Z, Xu J, Liu M. Tumor-derived miR-203a-3p potentiates muscle wasting by inducing muscle ferroptosis in pancreatic cancer. Cancer Lett 2025:217523. [PMID: 39921083 DOI: 10.1016/j.canlet.2025.217523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/26/2025] [Accepted: 02/01/2025] [Indexed: 02/10/2025]
Abstract
Pancreatic cancer (PC) cachexia, characterized by profound muscle wasting and systemic inflammation, remains a formidable clinical challenge due to its multifactorial nature and complex molecular underpinnings. This study delves into the intricate interplay between microRNA (miRNA) dysregulation and ferroptosis, a form of iron-dependent cell death, in PC cachexia. Specifically, we identified tumor-derived miR-203a-3p as a pivotal miRNA that promotes muscle atrophy by upregulating muscle ferroptosis. Our findings revealed that miR-203a-3p targets zinc finger E-box binding homeobox 1 (ZEB1), subsequently enhancing the expression of the iron transporter solute carrier family 11 member 2 (SLC11A2), thereby facilitating ferroptosis-associated skeletal muscle cell death. Through in vivo experiments using a PC cachexic mouse model, we demonstrated that inhibiting ferroptosis effectively attenuated muscle wasting, highlighting its critical role in the pathogenesis of PC cachexia. These results provide a molecular framework elucidating how miRNA regulation and ferroptosis converge to drive muscle atrophy, offering novel therapeutic avenues for mitigating cachexia in PC patients. By targeting these pathways, we aim to improve muscle preservation and overall survival in this devastating disease.
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Affiliation(s)
- Yumeng Hu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yifu Hu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shaobo Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuanyuan Guo
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Fangxia Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yongxing Du
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lijuan Wang
- Department of Clinical Nutrition, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100370, China
| | - Pengxue Li
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100370, China
| | - Yan Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital (Nansha division), Sun Yat-sen University, Guangzhou 510630, China
| | - Hui Zhang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zhikai Yang
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jingyong Xu
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100370, China.
| | - Mingyang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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3
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Li R, Ji Q, Fu S, Gu J, Liu D, Wang L, Yuan X, Wen Y, Dai C, Li H. ITGA3 promotes pancreatic cancer progression through HIF1α- and c-Myc-driven glycolysis in a collagen I-dependent autocrine manner. Cancer Gene Ther 2025; 32:240-253. [PMID: 39690180 DOI: 10.1038/s41417-024-00864-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 11/19/2024] [Accepted: 12/04/2024] [Indexed: 12/19/2024]
Abstract
Pancreatic cancer is characterized by severe metabolic stress due to its prominent desmoplasia and poor vascularization. Integrin subunit alpha 3 (ITGA3) is a cell surface adhesion protein involved in tumor progression. However, the role of ITGA3 in pancreatic cancer progression, especially in metabolic reprogramming, remains largely unknown. In this study, we found that ITGA3 expression is elevated in pancreatic cancer tissues and predicts poor prognosis for patients with pancreatic cancer. Functional assays revealed that ITGA3 promotes the growth and liver metastasis of pancreatic cancer via boosting glycolysis. Mechanistically, Collagen I (Col1) derived from cancer cells acts as a ligand for ITGA3 to activate the FAK/PI3K/AKT/mTOR signaling pathway in an autocrine manner, thereby increasing the expression of HIF1α and c-Myc, two critical regulators of glycolysis. Blockade of Col1 by siRNA or of ITGA3 by a blocking antibody leads to specific inactivation of the FAK/PI3K/AKT/mTOR pathway and impairs malignant tumor behaviors induced by ITGA3. Thus, our data indicate that ITGA3 enhances glycolysis to promote pancreatic cancer growth and metastasis via increasing HIF1α and c-Myc expression in a Col1-dependent autocrine manner, making ITGA3 as a candidate diagnostic biomarker and a potential therapeutic target for pancreatic cancer.
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Affiliation(s)
- Rongkun Li
- Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
| | - Qian Ji
- Department of Pulmonary Oncology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China
| | - Shengqiao Fu
- Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Jichun Gu
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Dejun Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Lu Wang
- Abdominal Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Xiao Yuan
- Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yi Wen
- Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Chunhua Dai
- Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
| | - Hengchao Li
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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4
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Xu X, Peng Q, Ren Z, Han Y, Jiang X, Wu Z, Tan S, Yang W, Oyang L, Luo X, Lin J, Xia L, Peng M, Wu N, Tang Y, Tian H, Zhou Y, Liao Q. CircRNF13 enhances IGF2BP1 phase separation-mediated ITGB1 mRNA stabilization in an m6A-dependent manner to promote oral cancer cisplatin chemoresistance. Mol Cancer 2025; 24:36. [PMID: 39891203 PMCID: PMC11783750 DOI: 10.1186/s12943-025-02239-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/18/2025] [Indexed: 02/03/2025] Open
Abstract
Oral cancer ranks among the most common malignancies within the head and neck region; however, its etiology remains inadequately understood despite substantial research advances in recent years. Many studies highlight the regulatory role of circular RNAs (circRNAs) in human cancers, suggesting their potential as cancer biomarkers. However, their specific mechanisms in oral cancer are not well understood. This study analyzed circRNAs expression in oral cancer, identifying circRNF13 (circbaseID: has_circ_0006801) as having elevated expression in oral cancer cells and tissues. Our study demonstrated that circRNF13 is correlated with increased tumor grade and stage in oral cancer. Results from both in vitro and in vivo experiments indicated that circRNF13 enhances cancer cell proliferation and tumor growth, while concurrently diminishing tumor sensitivity to cisplatin. Mechanistically, circRNF13 interacts with the m6A "reader" protein IGF2BP1, inhibiting its ubiquitin-mediated degradation and promoting its phase separation formation. Subsequently, circRNF13 augments the stability of ITGB1 mRNA via IGF2BP1 in a manner dependent on m6A modification. The m6A modification of ITGB1 mRNA is modulated by the phase separation of IGF2BP1, thereby promoting the malignant progression of oral cancer cells. This evidence positions circRNF13 as a crucial regulatory molecule in the pathogenesis of oral cancer and suggests its potential as a therapeutic target. This discovery enriches our understanding of the mechanistic role of circRNAs.
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Affiliation(s)
- Xuemeng Xu
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Qiu Peng
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Zongyao Ren
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Yaqian Han
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Xianjie Jiang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Zhu Wu
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Shiming Tan
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
| | - Wenjuan Yang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
| | - Linda Oyang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Xia Luo
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Jinguan Lin
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Longzheng Xia
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Mingjing Peng
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Nayiyuan Wu
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Yanyan Tang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China
| | - Hao Tian
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China.
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China.
| | - Yujuan Zhou
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, 410013, P. R. China.
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids Technology, 283 Tongzipo Road, Changsha, Hunan, 410013, P. R. China.
| | - Qianjin Liao
- Department of Oncology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, 410005, P. R. China.
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5
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Liu J, Zhang B, Huang B, Zhang K, Guo F, Wang Z, Shang D. A stumbling block in pancreatic cancer treatment: drug resistance signaling networks. Front Cell Dev Biol 2025; 12:1462808. [PMID: 39872846 PMCID: PMC11770040 DOI: 10.3389/fcell.2024.1462808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025] Open
Abstract
The primary node molecules in the cell signaling network in cancer tissues are maladjusted and mutated in comparison to normal tissues, which promotes the occurrence and progression of cancer. Pancreatic cancer (PC) is a highly fatal cancer with increasing incidence and low five-year survival rates. Currently, there are several therapies that target cell signaling networks in PC. However, PC is a "cold tumor" with a unique immunosuppressive tumor microenvironment (poor effector T cell infiltration, low antigen specificity), and targeting a single gene or pathway is basically ineffective in clinical practice. Targeted matrix therapy, targeted metabolic therapy, targeted mutant gene therapy, immunosuppressive therapy, cancer vaccines, and other emerging therapies have shown great therapeutic potential, but results have been disappointing. Therefore, we summarize the identified and potential drug-resistant cell signaling networks aimed at overcoming barriers to existing PC therapies.
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Affiliation(s)
- Jinming Liu
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Biao Zhang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bingqian Huang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou, China
| | - Kexin Zhang
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fujia Guo
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhizhou Wang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Pancreas and Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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6
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Shi Q, Yang Z, Yang H, Xu L, Xia J, Gu J, Chen M, Wang Y, Zhao X, Liao Z, Mou Y, Gu X, Xie T, Sui X. Targeting ion channels: innovative approaches to combat cancer drug resistance. Theranostics 2025; 15:521-545. [PMID: 39744692 PMCID: PMC11671388 DOI: 10.7150/thno.103384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 10/21/2024] [Indexed: 01/11/2025] Open
Abstract
Ion channels, as functional molecules that regulate the flow of ions across cell membranes, have emerged as a promising target in cancer therapy due to their pivotal roles in cell proliferation, metastasis, apoptosis, drug resistance, and so on. Recently, increasing evidence suggests that dysregulation of ion channels is a common characteristic of cancer cells, contributing to their survival and the resistance to conventional therapies. For example, the aberrant expression of sodium (Na+) and potassium ion (K+) channels is significantly correlated with the sensitivity of chemotherapy drugs. The endogenous calcium (Ca2+) channels contribute to the acquired resistance of osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer cell lines. Ferrous ions (Fe2+) enhance the sensitivity of breast cancer cells to doxorubicin treatment. Preclinical models have also demonstrated the effect of specific ion channel blockers or modulators on anticancer drug resistance. This review describes the current understanding about the interaction between ion channels and the therapeutic efficacy of anticancer drugs. Then, the therapeutic potential of ion channel blockers or modulators in enhancing the sensitivity or overcoming the resistance of cancer cells to anticancer therapies is discussed. Targeting ion channels will hopefully offer a novel and promising strategy for overcoming cancer drug resistance.
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Affiliation(s)
- Qian Shi
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zijing Yang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Huan Yang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Lihui Xu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jing Xia
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jie Gu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Mengting Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yan Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiaohong Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zehua Liao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yiping Mou
- General Surgery, Cancer Center, Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical University, Hangzhou, Zhejiang, China
| | - Xidong Gu
- Department of Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xinbing Sui
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
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7
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Xu R, Martinez-Bosch N, Rivera-Hueto F, Mulens-Arias V, Rubio-Moscardo F, Javier Conesa J, Navarro P, Vicente R, Rivera-Gil P. Validation of ZIP4 as a tumour-associated antigen for nanotargeting. J Drug Target 2025; 33:143-155. [PMID: 39283041 DOI: 10.1080/1061186x.2024.2405711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 09/06/2024] [Accepted: 09/12/2024] [Indexed: 10/02/2024]
Abstract
Pancreatic ductal adenocarcinoma remains a highly aggressive and untreatable cancer. There is a need to develop a new PDAC-associated antigen-targeting drug delivery system to tackle this disease. We validated choosing ZIP4 as a putative target in PDAC theranostics. We developed a nanosystem composed of a fluorescent polystyrene core coated with gold nanoparticles onto which a ZIP4-specific polyclonal antibody is attached. The polystyrene core's fluorescence properties allow the nanosystem tracking by intravital imaging. We also developed two ZIP4-expressing cell lines by stably transfecting HEK293 and RWP1 cells with a ZIP4-coding plasmid that simultaneously provides cells with puromycin resistance. We studied the cell internalisation of the as-synthesised nanoparticles and demonstrated that ZIP4-expressing HEK293 and ZIP4-expressing RWP1 cells tended to take up more ZIP4-targeting nanoparticles. Moreover, we observed that ZIP4-targeting nanoparticles accumulated more in ZIP4-expressing HEK293 and RWP1 tumours when injected intravenously in a subcutaneous xenograft and an orthotopic in vivo model, respectively. Furthermore, the administration of these nanoparticles did not induce any significant systemic toxicity as determined by histological analysis of all organs. Altogether, these results provide the first evidence of the feasibility of using a ZIP4-targeting nanosystem further to design efficient therapeutic and diagnostic tools for PDAC.
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Affiliation(s)
- Ruixue Xu
- Integrative Biomedical Materials and Nanomedicine Lab, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, PRBB, Barcelona, Spain
| | - Neus Martinez-Bosch
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
| | | | - Vladimir Mulens-Arias
- Integrative Biomedical Materials and Nanomedicine Lab, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, PRBB, Barcelona, Spain
| | - Fanny Rubio-Moscardo
- Molecular Physiology Lab, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, PRBB, Barcelona, Spain
| | - J Javier Conesa
- Mistral Beamline, Experiment Division, ALBA Synchrotron (ALBA-CELLS), Barcelona, Spain
| | - Pilar Navarro
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IIBB)-CSIC, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Rubén Vicente
- Molecular Physiology Lab, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, PRBB, Barcelona, Spain
| | - Pilar Rivera-Gil
- Integrative Biomedical Materials and Nanomedicine Lab, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, PRBB, Barcelona, Spain
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8
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Shao G, Xu J, Hu C, Jia W, Xu X, Gu Y, Zhang L, Zheng Z, Zhong J, Zhu S, Meng S, Zhao Z, Zhang Z, Liu J, Xu Y, Wu H. Podocyte YAP ablation decreases podocyte adhesion and exacerbates FSGS progression through α3β1 integrin. J Pathol 2025; 265:84-98. [PMID: 39668547 DOI: 10.1002/path.6370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/04/2024] [Accepted: 10/15/2024] [Indexed: 12/14/2024]
Abstract
Severe proteinuria in focal segmental glomerulosclerosis (FSGS) is closely associated with decreased adhesion, and subsequent loss, of podocytes. Yes-associated protein (YAP) is a key transcriptional coactivator that plays a significant role in maintaining cellular homeostasis. However, its role in podocyte adhesion and its specific mechanism in FSGS progression remain unclear. In this study, an adriamycin (ADR)-induced FSGS model was established using podocyte-specific Yap knockout (KO) mice and control mice. These mice were further treated with Pyrintegrin, an agonist of α3β1 integrin, or a vehicle. Additionally, an ADR-induced FSGS model was constructed using podocyte-specific Itga3 KO mice, which were subsequently treated with 1-oleoyl lysophosphatidic acid (LPA), a YAP activator, or a vehicle. Our findings demonstrated that YAP was positively correlated with podocyte adhesion. Podocyte-specific Yap KO mice exhibited reduced levels of α3β1 integrin and podocyte adhesion. Yap KO aggravated the ADR-induced reduction in α3β1 integrin and podocyte adhesion, resulting in significantly increased segmental or global glomerulosclerosis and proteinuria. Notably, treatment with a β1 integrin agonist partially ameliorated the decrease of podocyte adhesion and the worsening FSGS progression caused by Yap KO. Mechanistically, YAP was found to transcriptionally regulate α3- and β1 integrin via transcriptional enhanced associate domain 3 (TEAD3), with TEAD3 binding to the promoter region of Itga3. Furthermore, Itga3 KO or knockdown abolished the beneficial effects of YAP activation on podocyte adhesion and FSGS progression. In conclusion, our results demonstrate that YAP regulates podocyte adhesion and FSGS progression through its transcriptional regulation of α3β1 integrin via TEAD3. This suggests that the YAP-TEAD3-α3β1 integrin axis may serve as a promising therapeutic target for FSGS. © 2024 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Guangze Shao
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Jitu Xu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Chencheng Hu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Wenyao Jia
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Xitong Xu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Yue Gu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Luming Zhang
- School of Biological Sciences, College of Life Science, Northwest A&F University, Xianyang, PR China
| | - Zhihuang Zheng
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Jiayan Zhong
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Siqi Zhu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Shenghao Meng
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Zhonghua Zhao
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Zhigang Zhang
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
| | - Jun Liu
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Yanyong Xu
- Frontier Innovation Center of School of Basic Medical Sciences, Fudan University, Shanghai, PR China
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai, PR China
| | - Huijuan Wu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Kidney and Dialysis Institute of Shanghai, Shanghai, PR China
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9
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Yao S, Nguyen TD, Lan Y, Yang W, Chen D, Shao Y, Yang Z. MetaPhenotype: A Transferable Meta-Learning Model for Single-Cell Mass Spectrometry-Based Cell Phenotype Prediction Using Limited Number of Cells. Anal Chem 2024; 96:19238-19247. [PMID: 39570119 DOI: 10.1021/acs.analchem.4c02038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Single-cell mass spectrometry (SCMS) is an emerging tool for studying cell heterogeneity according to variation of molecular species in single cells. Although it has become increasingly common to employ machine learning models in SCMS data analysis, such as the classification of cell phenotypes, the existing machine learning models often suffer from low adaptability and transferability. In addition, SCMS studies of rare cells can be restricted by limited number of cell samples. To overcome these limitations, we performed SCMS analyses of melanoma cancer cell lines with two phenotypes (i.e., primary and metastatic cells). We then developed a meta-learning-based model, MetaPhenotype, that can be trained using a small amount of SCMS data to accurately classify cells into primary or metastatic phenotypes. Our results show that compared with standard transfer learning models, MetaPhenotype can rapidly predict and achieve a high accuracy of over 90% with fewer new training samples. Overall, our work opens the possibility of accurate cell phenotype classification based on fewer SCMS samples, thus lowering the demand for sample acquisition.
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Affiliation(s)
- Songyuan Yao
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Tra D Nguyen
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Yunpeng Lan
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Wen Yang
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Dan Chen
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Yihan Shao
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Zhibo Yang
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
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10
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Wei D, Yuan L, Xu X, Wu C, Huang Y, Zhang L, Zhang J, Jing T, Liu Y, Wang B. Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-β-catenin axis in modulating gemcitabine resistance in pancreatic cancer. Cancer Lett 2024; 605:217284. [PMID: 39366545 DOI: 10.1016/j.canlet.2024.217284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/06/2024]
Abstract
Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.
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MESH Headings
- Gemcitabine
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Humans
- Drug Resistance, Neoplasm/genetics
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/metabolism
- Epigenesis, Genetic
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- beta Catenin/genetics
- beta Catenin/metabolism
- Cell Line, Tumor
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Enhancer Elements, Genetic
- Wnt Signaling Pathway/genetics
- Wnt Signaling Pathway/drug effects
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Affiliation(s)
- Dianhui Wei
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Lili Yuan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Xiaoli Xu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Chengsi Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Yiwen Huang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Lili Zhang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jilong Zhang
- Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, China.
| | - Tiantian Jing
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
| | - Yizhen Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Boshi Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
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11
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Tan W, Chen G, Ci Q, Deng Z, Gu R, Yang D, Dai F, Liu H, Cheng Y. Elevated ITGA3 expression serves as a novel prognostic biomarker and regulates tumor progression in cervical cancer. Sci Rep 2024; 14:27063. [PMID: 39511266 PMCID: PMC11543847 DOI: 10.1038/s41598-024-75770-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Patients with advanced and recurrent cervical cancer often lack satisfactory treatment outcomes. Thus, it is necessary to seek reliable biomarkers that provide the ability to identify the disease at an early stage and predict the patient prognosis, providing new strategies for the treatment of cervical cancer. The sequencing data of ITGA3 were retrieved from public datasets. Immune infiltration and sensitivity of potential immunotherapy and chemotherapy have been analyzed between two subgroups. Functional analysis was applied to excavate the related pathways of ITGA3 in cervical cancer. Furthermore, the impact of ITGA3 in tumor progression has been verified in vitro. The results revealed that the level of ITGA3 was upregulated in cervical cancer, and was positively correlated with worse prognosis. The tumor microenvironment of patients in the high-risk group was immunosuppressed. Patients in high-risk group may not benefit from immunotherapy, but be may be sensitive to several chemotherapy drugs. Notably, the angiogenesis, epithelial mesenchymal transition, and PI3K pathway were increased in high-risk group. Collectively, ITGA3 is a marker of poor prognosis and promotes tumor progression by regulating PI3K/AKT pathway in cervical cancer. Our results provide new insights for potential molecular targeted therapy and prognostic prediction of cervical cancer.
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Affiliation(s)
- Wei Tan
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China
| | - Gantao Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Qinyu Ci
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China
| | - Zhimin Deng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China
| | - Ran Gu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China
| | - Dongyong Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China
| | - Fangfang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.
| | - Hua Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.
| | - Yanxiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.
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12
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Guo H, Wang S, Zhang H, Li J, Wang C, Liu Z, Chen J, Wang K, Wei X, Wei Q, Xu X. Research progress on the molecular structure, function, and application in tumor therapy of zinc transporter ZIP4. Int J Biol Sci 2024; 20:5910-5924. [PMID: 39664563 PMCID: PMC11628325 DOI: 10.7150/ijbs.102460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/22/2024] [Indexed: 12/13/2024] Open
Abstract
ZIP4, a pivotal member of the ZIP family, is the causative gene for the hereditary disorder AE (acrodermatitis enteropathica) in humans, and plays an essential role in regulating zinc ion balance within cells. While research on the molecular structure of ZIP4 continues, there remains a lack of full understanding regarding the stereo-structural conformation of ZIP4 molecules. Currently, there are two hypotheses concerning the transport of zinc ions into the cytoplasm by ZIP4, with some contradictions between experimental studies. Recent investigations have revealed that ZIP4 is involved in tumor growth, metastasis, drug tolerance, and various other processes. Most studies suggest that ZIP4 regulates the malignant biological behavior of tumors through zinc ions as a second messenger: however, latest research has identified that ZIP4 itself binds to Ephrin-B1 to regulate tumor metastasis. This review provides a comprehensive summary of the molecular structure of ZIP4 and its mechanism for transporting zinc ions while also exploring mutual regulation between zinc ions and ZIP4. Furthermore, it summarizes recent research progress on the role of ZIP4 in tumors and discusses its potential as a target for anticancer therapy based on an extensive analysis of research findings. These insights can guide future investigations into the role of ZIP4 in tumors.
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Affiliation(s)
- Haijun Guo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Shaohua Wang
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Shaoxing city Keqiao District TCM hospital Medical Alliance General Hospital, Shaoxing, 312000, China
| | - Hui Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medicine University, Hangzhou, 310053, China
| | - Jie Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Chao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital Affiliated to Hangzhou Medical College (Zhejiang Provincial People's Hospital), Hangzhou, 310024, China
| | - Jun Chen
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital Affiliated to Hangzhou Medical College (Zhejiang Provincial People's Hospital), Hangzhou, 310024, China
| | - Kai Wang
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital Affiliated to Hangzhou Medical College (Zhejiang Provincial People's Hospital), Hangzhou, 310024, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital Affiliated to Hangzhou Medical College (Zhejiang Provincial People's Hospital), Hangzhou, 310024, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital Affiliated to Hangzhou Medical College (Zhejiang Provincial People's Hospital), Hangzhou, 310024, China
- Institute of Translational Medical, Zhejiang University, Hangzhou, 310006, China
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13
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Guo H, Su R, Lu X, Zhang H, Wei X, Xu X. ZIP4 inhibits Ephrin-B1 ubiquitination, activating Wnt5A/JNK/ZEB1 to promote liver cancer metastasis. Genes Dis 2024; 11:101312. [PMID: 39040931 PMCID: PMC11260364 DOI: 10.1016/j.gendis.2024.101312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 04/03/2024] [Indexed: 07/24/2024] Open
Affiliation(s)
- Haijun Guo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
| | - Renyi Su
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Xinfeng Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang 310053, China
| | - Hui Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang 310053, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
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14
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Jia Q, Zhu Y, Yao H, Yin Y, Duan Z, Zheng J, Ma D, Yang M, Yang J, Zhang J, Liu D, Hua R, Huo Y, Fu X, Sun Y, Liu W. Oncogenic GALNT5 confers FOLFIRINOX resistance via activating the MYH9/ NOTCH/ DDR axis in pancreatic ductal adenocarcinoma. Cell Death Dis 2024; 15:767. [PMID: 39433745 PMCID: PMC11493973 DOI: 10.1038/s41419-024-07110-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 09/16/2024] [Accepted: 09/24/2024] [Indexed: 10/23/2024]
Abstract
Chemotherapy resistance has been a great challenge in pancreatic ductal adenocarcinoma(PDAC) treatments. Current first-line chemotherapy regimens for PDAC include gemcitabine-based regimens such as AG regimen (albumin paclitaxel and gemcitabine), fluorouracil-based regiments such as FOLFIRINOX regimen ((5-fluorouracil5-FU), oxaliplatin, Irinotecan) and platinum-based regimens for patients with BRCA mutations. large amounts of work have been done on exploring the mechanism underlying resistance of gemcitabine-based and platinum-based regimens, while little research has been achieved on the mechanism of FOLFIRINOX regimens resistance. Hence, we identified Polypeptide N-Acetylgalactosaminyltransferase 5, (GALNT5) as a vital regulator and a potential therapeutic target in FOLFIRINOX regimens resistance. Colony formation assays and flow cytometry assays were performed to explore the roles of GALNT5 in cell proliferation and apoptosis in PDAC treated with FOLFIRINOX. IC50 alterations were calculated in GALNT5 knockdown and overexpressed cell lines. RNA-seq followed by GSEA (gene set enrichment analysis) was displayed to explore the potential mechanism. WB (western blotting), real-time PCR, and IF (immunofluorescence) were performed to validate relative pathways. The mouse orthotopic xenograft PDAC model was established to examine GALNT5 functions in vivo. GALNT5 was highly expressed in PDAC tissues and predicted poor prognosis in PDAC. Upregulation of GALNT5 in PDAC cells conferred FOLFIRINOX resistance on PDAC by inhibiting DNA damage. Moreover, GALNT5 interacted with MYH9, thus participating in the activation of the NOTCH pathways, resulting in hampering FOI-induced DNA damage. Functions of GALNT5 promoting FOLFIRINOX resistance were validated in vivo. In this study, we found that aberrantly overexpressed GALNT5 in PDAC took part in the activation of the NOTCH pathway by interacting with MYH9, thus inhibiting the DDR to achieve FOLFIRINOX resistance and causing poor prognosis. We identified GALNT5 as a potential therapeutic target for PDAC patients resistant to FOLFIRINOX chemotherapy.
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MESH Headings
- Humans
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- N-Acetylgalactosaminyltransferases/metabolism
- N-Acetylgalactosaminyltransferases/genetics
- Oxaliplatin/pharmacology
- Oxaliplatin/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Animals
- Fluorouracil/pharmacology
- Fluorouracil/therapeutic use
- Leucovorin/pharmacology
- Leucovorin/therapeutic use
- Mice
- Cell Line, Tumor
- Polypeptide N-acetylgalactosaminyltransferase
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/metabolism
- Receptors, Notch/metabolism
- Irinotecan/pharmacology
- Irinotecan/therapeutic use
- Mice, Nude
- Cell Proliferation/drug effects
- Apoptosis/drug effects
- Signal Transduction/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Female
- Xenograft Model Antitumor Assays
- Myosin Heavy Chains
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Affiliation(s)
- Qinyuan Jia
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Yuheng Zhu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Hongfei Yao
- Department of Hepato-Biliary-Pancreatic Surgery, General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, P.R. China
| | - Yifan Yin
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Zonghao Duan
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Jiahao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China
| | - Ding Ma
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Minwei Yang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Jianyu Yang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Junfeng Zhang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Dejun Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Rong Hua
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China
| | - Yanmiao Huo
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
| | - Xueliang Fu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
| | - Yongwei Sun
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
| | - Wei Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
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15
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Li B, Xing F, Wang J, Wang X, Zhou C, Fan G, Zhuo Q, Ji S, Yu X, Xu X, Qin Y, Li Z. YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer. Cancer Lett 2024; 602:217197. [PMID: 39216548 DOI: 10.1016/j.canlet.2024.217197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 07/30/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.
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Affiliation(s)
- Borui Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Faliang Xing
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jingyi Wang
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD 4067, Australia
| | - Xiaohong Wang
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Chenjie Zhou
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Guixiong Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Qifeng Zhuo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Zheng Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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Tang Y, Guo S, Yu N, Li H. ZIP4: a promising early diagnostic and therapeutic targets for pancreatic cancer. Am J Cancer Res 2024; 14:4652-4664. [PMID: 39417191 PMCID: PMC11477812 DOI: 10.62347/avym3477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 09/15/2024] [Indexed: 10/19/2024] Open
Abstract
Pancreatic cancer is an aggressive and metastatic tumor that lacks effective early detection and treatment methods. There is an urgent need to further understand its underlying molecular mechanisms and identify new biomarkers for early detection. Zinc, a critical trace element and catalytic cofactor, is tightly regulated within cells. ZIP4, a zinc transporter protein significantly overexpressed in human pancreatic cancer, appears to play a pivotal role in tumor development by modulating intracellular zinc concentration. This review highlights the role of ZIP4 in tumorigenesis, including its impact on pancreatic cancer growth, proliferation, migration, and drug resistance. ZIP4 exerts its effects by regulating zinc dependent transcriptional factors like CREB, STAT3, and ZEB1, resulting in upregulation of Cyclin D1, TP53INP1, ITGA3, CD44, ENT1 proteins, and miR-373. Moreover, ZIP4 mediates the miR373-PHLPP2-AKT signaling axis, which increases TGF-β expression. Coupled with CREB-activated macrophage catabolism-related genes SDC1 and DNM2, ZIP4 promotes cancer cachexia and supports amino acids to tumor cells under metabolic stress. Furthermore, ZIP4 facilitates bone resorption by osteoclasts via the RANKL-activated NF-κB pathway. A deeper understanding of these mechanisms may unveil potential targets for early diagnosis, prognosis assessment, and dietary recommendations for pancreatic cancer. These findings hold clinical significance not only for pancreatic cancer but also for other malignancies exhibiting heightened ZIP4 expression.
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Affiliation(s)
- Yunpeng Tang
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, PR China
| | - Sheng Guo
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, PR China
| | - Nianhui Yu
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, PR China
| | - Hui Li
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, PR China
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17
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Huang S, Hu J, Hu M, Hou Y, Zhang B, Liu J, Liu X, Chen Z, Wang L. Cooperation between SIX1 and DHX9 transcriptionally regulates integrin-focal adhesion signaling mediated metastasis and sunitinib resistance in KIRC. Oncogene 2024; 43:2951-2969. [PMID: 39174859 DOI: 10.1038/s41388-024-03126-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 08/24/2024]
Abstract
High invasive capacity and acquired tyrosine kinase inhibitors (TKI) resistance of kidney renal clear cell carcinoma (KIRC) cells remain obstacles to prolonging the survival time of patients with advanced KIRC. In the present study, we reported that sine oculis homeobox 1 (SIX1) was upregulated in sunitinib-resistant KIRC cells and metastatic KIRC tissues. Subsequently, we found that SIX1 mediated metastasis and sunitinib resistance via Focal adhesion (FA) signaling, and knockdown of SIX1 enhanced the antitumor efficiency of sunitinib in KIRC. Mechanistically, Integrin subunit beta 1 (ITGB1), an upstream gene of FA signaling, was a direct transcriptional target of SIX1. In addition, we showed that DExH-box helicase 9 (DHX9) was an important mediator for SIX1-induced ITGB1 transcription, and silencing the subunits of SIX1/DHX9 complex significantly reduced transcription of ITGB1. Downregulation of SIX1 attenuated nuclear translocation of DHX9 and abrogated the binding of DHX9 to ITGB1 promoter. Collectively, our results unveiled a new signal axis SIX1/ITGB1/FAK in KIRC and identified a novel therapeutic strategy for metastatic KIRC patients.
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Affiliation(s)
- Shiyu Huang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Central Laboratory, Renmin Hospital of Wuhan University, 430060, Wuhan, Hubei, China
| | - Juncheng Hu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Min Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Yanguang Hou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Banghua Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Hubei Key Laboratory of Digestive System Disease, Wuhan, 430060, China
| | - Jiachen Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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18
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Liu D, van der Zalm AP, Koster J, Bootsma S, Oyarce C, van Laarhoven HWM, Bijlsma MF. Predictive biomarkers for response to TGF- β inhibition in resensitizing chemo(radiated) esophageal adenocarcinoma. Pharmacol Res 2024; 207:107315. [PMID: 39059615 DOI: 10.1016/j.phrs.2024.107315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/26/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-β) can induce this process. Inhibitors of TGF-β may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-β targeting. In vitro approximations of neoadjuvant treatment were applied to publicly available primary EAC cell lines. TGF-β inhibitors fresolimumab and A83-01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy. Our results demonstrated a robust induction of mesenchymal cell states following chemoradiation, with TGF-β inhibition leading to variable reductions in mesenchymal markers. The cell lines were clustered into responders and non-responders. Genomic expression profiles were obtained through RNA-seq analysis. Differentially expressed gene (DEG) analysis identified 10 positively- and 23 negatively-associated hub genes, which were bioinformatically identified. Furthermore, the correlation of DEGs with response to TGF-β inhibition was examined using public pharmacogenomic databases, revealing 9 positively associated and 11 negatively associated DEGs. Among these, ERBB2, EFNB1, and TNS4 were the most promising candidates. Our findings reveal a distinct gene expression pattern associated with the response to TGF-β inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-β targeting.
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Affiliation(s)
- Dajia Liu
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Amber P van der Zalm
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Jan Koster
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Sanne Bootsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Cesar Oyarce
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Hanneke W M van Laarhoven
- Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Maarten F Bijlsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands.
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Chen K, Li T, Diao H, Wang Q, Zhou X, Huang Z, Wang M, Mao Z, Yang Y, Yu W. SIRT7 knockdown promotes gemcitabine sensitivity of pancreatic cancer cell via upregulation of GLUT3 expression. Cancer Lett 2024; 598:217109. [PMID: 39002692 DOI: 10.1016/j.canlet.2024.217109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/04/2024] [Accepted: 07/04/2024] [Indexed: 07/15/2024]
Abstract
Gemcitabine serves as a first-line chemotherapeutic treatment for pancreatic cancer (PC), but it is prone to rapid drug resistance. Increasing the sensitivity of PC to gemcitabine has long been a focus of research. Fasting interventions may augment the effects of chemotherapy and present new options. SIRT7 is known to link metabolism with various cellular processes through post-translational modifications. We found upregulation of SIRT7 in PC cells is associated with poor prognosis and gemcitabine resistance. Cross-analysis of RNA-seq and ATAC-seq data suggested that GLUT3 might be a downstream target gene of SIRT7. Subsequent investigations demonstrated that SIRT7 directly interacts with the enhancer region of GLUT3 to desuccinylate H3K122. Our group's another study revealed that GLUT3 can transport gemcitabine in breast cancer cells. Here, we found GLUT3 KD reduces the sensitivity of PC cells to gemcitabine, and SIRT7 KD-associated gemcitabine-sensitizing could be reversed by GLUT3 KD. While fasting mimicking induced upregulation of SIRT7 expression in PC cells, knocking down SIRT7 enhanced sensitivity to gemcitabine through upregulating GLUT3 expression. We further confirmed the effect of SIRT7 deficiency on the sensitivity of gemcitabine under fasting conditions using a mouse xenograft model. In summary, our study demonstrates that SIRT7 can regulate GLUT3 expression by binding to its enhancer and altering H3K122 succinylation levels, thus affecting gemcitabine sensitivity in PC cells. Additionally, combining SIRT7 knockdown with fasting may improve the efficacy of gemcitabine. This unveils a novel mechanism by which SIRT7 influences gemcitabine sensitivity in PC and offer innovative strategies for clinical combination therapy with gemcitabine.
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Affiliation(s)
- Keyu Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Tiane Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Honglin Diao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Qikai Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Xiaojia Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Zhihua Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Mingyue Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China
| | - Zebin Mao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China.
| | - Yinmo Yang
- Department of General Surgery, Peking University First Hospital, Beijing, 100034, China.
| | - Wenhua Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, 100191, China.
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20
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Ou G, Tian Z, Su M, Yu M, Gong J, Chen Y. Identification of gemcitabine resistance-related AHNAK2 gene associated with prognosis and immune infiltration in pancreatic cancer. Heliyon 2024; 10:e33687. [PMID: 39040243 PMCID: PMC11261888 DOI: 10.1016/j.heliyon.2024.e33687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/25/2024] [Accepted: 06/25/2024] [Indexed: 07/24/2024] Open
Abstract
Purpose Gemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC. Methods In this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2. Results AHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages. Conclusions Our study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.
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Affiliation(s)
- Guangsheng Ou
- Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510600, PR China
| | - Zhenfeng Tian
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
| | - Mingxin Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
| | - Miao Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
| | - Jin Gong
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, 510632, PR China
| | - Yinting Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
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21
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Liu M, Ren Y, Zhou Z, Yang J, Shi X, Cai Y, Arreola AX, Luo W, Fung KM, Xu C, Nipp RD, Bronze MS, Zheng L, Li YP, Houchen CW, Zhang Y, Li M. The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia. Cancer Cell 2024; 42:885-903.e4. [PMID: 38608702 PMCID: PMC11162958 DOI: 10.1016/j.ccell.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 12/18/2023] [Accepted: 03/15/2024] [Indexed: 04/14/2024]
Abstract
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
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Affiliation(s)
- Mingyang Liu
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yu Ren
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Jingxuan Yang
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Xiuhui Shi
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yang Cai
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Alex X Arreola
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Wenyi Luo
- Department of Pathology, Yale School of Medicine, New Haven, CT 06519, USA
| | - Kar-Ming Fung
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Chao Xu
- Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Ryan D Nipp
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Michael S Bronze
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Lei Zheng
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Yi-Ping Li
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Courtney W Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yuqing Zhang
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Min Li
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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22
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Fan C, Xiong F, Zhang S, Gong Z, Liao Q, Li G, Guo C, Xiong W, Huang H, Zeng Z. Role of adhesion molecules in cancer and targeted therapy. SCIENCE CHINA. LIFE SCIENCES 2024; 67:940-957. [PMID: 38212458 DOI: 10.1007/s11427-023-2417-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/17/2023] [Indexed: 01/13/2024]
Abstract
Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.
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Affiliation(s)
- Chunmei Fan
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Fang Xiong
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, 410078, China
| | - Shanshan Zhang
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, 410078, China
| | - Zhaojian Gong
- Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - Can Guo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, China.
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, China.
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23
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Liu H, Li L, Lu R. ZIP transporters-regulated Zn 2+ homeostasis: A novel determinant of human diseases. J Cell Physiol 2024; 239:e31223. [PMID: 38530191 DOI: 10.1002/jcp.31223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/16/2024] [Accepted: 02/06/2024] [Indexed: 03/27/2024]
Abstract
As an essential trace element for organisms, zinc participates in various physiological processes, such as RNA transcription, DNA replication, cell proliferation, and cell differentiation. The destruction of zinc homeostasis is associated with various diseases. Zinc homeostasis is controlled by the cooperative action of zinc transporter proteins that are responsible for the influx and efflux of zinc. Zinc transporter proteins are mainly categorized into two families: Zrt/Irt-like protein (SLC39A/ZIP) family and zinc transporter (SLC30A/ZNT) family. ZIP transporters contain 14 members, namely ZIP1-14, which can be further divided into four subfamilies. Currently, ZIP transporters-regulated zinc homeostasis is one of the research hotspots. Cumulative evidence suggests that ZIP transporters-regulated zinc homeostasis may cause physiological dysfunction and contribute to the onset and progression of diverse diseases, such as cancers, neurological diseases, and cardiovascular diseases. In this review, we initially discuss the structure and distribution of ZIP transporters. Furthermore, we comprehensively review the latest research progress of ZIP transporters-regulated zinc homeostasis in diseases, providing a new perspective into new therapeutic targets for treating related diseases.
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Affiliation(s)
- Huimei Liu
- Department of Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
| | - Lanfang Li
- Department of Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Ruirui Lu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
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24
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Tan H, Liu J, Li Y, Mi Z, Liu B, Rong P. CCDC25 suppresses clear cell renal cell carcinoma progression by LATS1/YAP-mediated regulation of the hippo pathway. Cancer Cell Int 2024; 24:124. [PMID: 38570766 PMCID: PMC10988808 DOI: 10.1186/s12935-024-03318-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/29/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent renal cancers, and the molecular mechanisms underlying its progression are still not fully understood. The expression of CCDC25, a notably underexpressed gene in many tumors, has been understudied in ccRCC. This research aims to explore the role of CCDC25 in ccRCC's clinical outcomes and uncover the molecular pathways influenced by it. METHODS A multi-tiered approach was adopted involving bioinformatic analysis, tissue sample evaluation, in vitro and in vivo experiments. CCDC25 expression levels in tumor vs. normal tissues were quantified using Western blot and immunofluorescence studies. Cell proliferation and migration were analyzed using CCK8, EDU, Transwell assays, and wound healing assays. RNA sequencing was performed to elucidate the molecular pathways affected, followed by detailed protein-protein interaction studies and mouse xenograft models. RESULTS CCDC25 was predominantly underexpressed in ccRCC tumors and associated with advanced clinical stages and poor prognosis. Overexpression of CCDC25 in renal cancer cell lines resulted in reduced proliferation and migration. RNA sequencing revealed significant alterations in the Hippo pathway. Overexpression of CCDC25 inhibited the expression of downstream Hippo pathway proteins ITGA3 and CCND1 and promoted YAP phosphorylation. Mechanistic studies showed that CCDC25 interacts with YAP and influences YAP phosphorylation through LATS1. In vivo, CCDC25 overexpression inhibited tumor growth and promoted apoptosis. CONCLUSION CCDC25 acts as a potential tumor suppressor in ccRCC by inhibiting cell proliferation and migration, potentially through regulating the Hippo signaling pathway. These findings highlight the potential of CCDC25 as a therapeutic target in ccRCC treatment.
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Affiliation(s)
- Hongpei Tan
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410000, China
| | - Jiahao Liu
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410000, China
| | - Yanan Li
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410000, China
| | - Ze Mi
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410000, China
| | - Baiying Liu
- Department of Gastrointestinal Surgery, Third Xiangya Hospital, Central South University, Changsha, China.
| | - Pengfei Rong
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410000, China.
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25
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Liu Y, Deng Y, Constanthin PE, Li F. Ultrasound-targeted microbubble destruction improves the suppression and magnetic resonance imaging of pancreatic cancer with polyethyleneimine nanogels. J Cancer 2024; 15:2880-2890. [PMID: 38706910 PMCID: PMC11064254 DOI: 10.7150/jca.93802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 02/22/2024] [Indexed: 05/07/2024] Open
Abstract
The chemoresistance of pancreatic cancer tumors urgently needs to be addressed. Pancreatic cancer is characterized by an abundant stroma, with significant fibrous connective tissue formation that encapsulates the tumor parenchyma and forms an interstitial microenvironment. Pancreatic stellate cells (PSCs) play a crucial role in this microenvironment and specially secrete periosteal protein (periostin), which can promote tumor growth, metastasis, and chemoresistance. Therefore, periostin has become a specific target of chemotherapy resistance intervention methods. The proposed polyethyleneimine (PEI) nanogels have multiple modification and efficient drug-loading properties. Additionally, ultrasound-targeted microbubble destruction (UTMD) supports the breakdown of the tough interstitial barrier of pancreatic cancer. A small interfering RNA (siRNA) can be used to downregulated the periostin gene, while sustained release of gemcitabine can promote killing of tumor cells. This method achieves a combination of gene silencing and chemotherapy. The imaging effect can be evaluated using magnetic resonance imaging (MRI). The ultimate goal of this work is to support individualized and effective therapeutic methods and help develop new strategies for pancreatic cancer treatment.
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Affiliation(s)
- Yang Liu
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuanqiong Deng
- Department of Ultrasound, Maternal and Child Health Hospital of Shanghai Jiading District, Shanghai, China
| | - Paul E Constanthin
- CHU Pellegrin, Service de Neurochirurgie B, Hôpital Pellegrin-Tripode, Place Amélie Raba-Léon, 33 076, Bordeaux Cedex, France
| | - Fan Li
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Zhai LL, Li WB, Chen LJ, Wang W, Ju TF, Yin DL. Curcumin inhibits the invasion and migration of pancreatic cancer cells by upregulating TFPI-2 to regulate ERK- and JNK-mediated epithelial-mesenchymal transition. Eur J Nutr 2024; 63:639-651. [PMID: 38129361 DOI: 10.1007/s00394-023-03296-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
PURPOSE Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.
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Affiliation(s)
- Lu-Lu Zhai
- Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, People's Republic of China
- Department of General Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, People's Republic of China
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Wei-Bo Li
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Long-Jiang Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Wei Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Tong-Fa Ju
- Department of General Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, People's Republic of China.
| | - Da-Long Yin
- Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, People's Republic of China.
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Ma Y, Zhang L, Gao X, Zhu D. GPX3 represses pancreatic cancer cell proliferation, migration and invasion, and improves their chemo‑sensitivity by regulating the JNK/c‑Jun signaling pathway. Exp Ther Med 2024; 27:118. [PMID: 38361519 PMCID: PMC10867734 DOI: 10.3892/etm.2024.12407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 11/22/2023] [Indexed: 02/17/2024] Open
Abstract
Pancreatic cancer (PC) is a deadly and aggressive disease, which is characterized by poor prognosis. It has been reported that glutathione peroxidase 3 (GPX3) is involved in the development of several types of cancer. The present study aimed to explore the regulatory role of GPX3 in PC and uncover its underlying mechanism. Bioinformatics analysis was initially carried out to predict the expression profile of GPX3 in PC and its association with prognosis. The expression levels of GPX3 were also detected in PC cells by reverse transcription-quantitative PCR and western blot analysis. Following transfection to induce GPX3 overexpression, the proliferation ability of PC cells was assessed by Cell Counting Kit-8, colony formation and 5-ethynyl-2'-deoxyuridine incorporation assays. In addition, wound healing and Transwell assays were performed to evaluate the migration and invasion abilities of PC cells. Cell apoptosis was assessed by flow cytometric analysis. The expression levels of epithelial-mesenchymal transition (EMT)-, apoptosis-, and JNK signaling-related proteins were detected by western blot analysis. Additionally, for rescue experiments, JNK signaling was activated following cell treatment with anisomycin. The results showed that GPX3 was downregulated in PC and its expression was associated with favorable prognosis. In addition, cell transfection-induced GPX3 overexpression markedly inhibited cell proliferation, migration and invasion, and inhibited EMT. In addition, GPX3 improved the chemo-sensitivity of PC and gemcitabine (GEM)-resistant PC cells to GEM. Furthermore, GPX3 significantly suppressed JNK/c-Jun signaling in PC, while anisomycin treatment reversed the inhibitory effects of GPX3 on the malignant behavior and chemo-resistance of PC cells. The results of the present study indicated that GPX3 could serve as a tumor suppressor in PC via inhibiting JNK/c-Jun signaling, thus providing novel insights into the treatment of PC.
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Affiliation(s)
- Ye Ma
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
| | - Lixing Zhang
- Medical Laboratory, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, P.R. China
| | - Xin Gao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Dongming Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Zhao YC, Wang TJ, Cui J, She LZ, Zhang RF, Zhang CH. The role of SLC39A4 in the prognosis, immune microenvironment, and contribution to malignant behavior in vivo and in vitro of cervical cancer. Transl Oncol 2024; 40:101839. [PMID: 38029507 PMCID: PMC10698533 DOI: 10.1016/j.tranon.2023.101839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) are becoming more common in younger women. Solute carrier family 39 member 4 (SLC39A4) produces a zinc ion transporter involved in metastasis and invasion of tumors. METHODS The Cancer Genome Atlas RNA-seq data was used to investigate the expression of SLC39A4 and its prognostic potential. The assessment of the effect of SLC39A4 on cell growth and migration in CESC was conducted using MTT, colony formation, and Transwell assays. SLC39A4 was studied in vivo using a xenograft mouse model, and its functional involvement in oncogenesis was investigated by identifying the associated differentially expressed genes (DEGs). We evaluated the relationships among SLC39A4 levels, chemosensitivity, radiosensitivity and immune infiltration. RESULTS SLC39A4 was upregulated in CESC samples, and individuals with greater SLC39A4 mRNA expression had shorter overall survival. SLC39A4 has been identified to be a regulator of tumor cell metastasis and proliferation in vivo and in vitro, with an area under the curve of 0.874 for diagnosing CESC. In total, 948 DEGs were discovered to be enriched in key CESC progression-related signaling pathways. Additionally, intratumoral immune checkpoint and infiltration activity were associated with SLC39A4 expression. High SLC39A4 expression exhibited poor chemosensitivity and radiosensitivity profiles. CONCLUSION In conclusion, SLC39A4 is a key regulator of CESC development, prognosis, and the composition of the tumor immune microenvironment. SLC39A4 could be used as a prognostic or diagnostic screening tool and as a potential target for CESC treatment.
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Affiliation(s)
- Yue-Chen Zhao
- Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China
| | - Tie-Jun Wang
- Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China
| | - Jie Cui
- Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China
| | - Li-Zhen She
- Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China
| | - Rui-Feng Zhang
- Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China; Department of Internal Medicin-1, Jilin Cancer Hospital, Changchun, Jilin 130103, PR China
| | - Chao-He Zhang
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130041, PR China.
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Li X, Kong R, Hou W, Cao J, Zhang L, Qian X, Zhao L, Ying W. Integrative proteomics and n-glycoproteomics reveal the synergistic anti-tumor effects of aspirin- and gemcitabine-based chemotherapy on pancreatic cancer cells. Cell Oncol (Dordr) 2024; 47:141-156. [PMID: 37639207 DOI: 10.1007/s13402-023-00856-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2023] [Indexed: 08/29/2023] Open
Abstract
OBJECTIVE AND DESIGN Pancreatic cancer is a highly malignant tumor that is well known for its poor prognosis. Based on glycosylation, we performed integrated quantitative N-glycoproteomics to investigate the synergistic anti-tumor effects of aspirin and gemcitabine on pancreatic cancer cells and explore the potential molecular mechanisms of chemotherapy in pancreatic cancer. METHODS AND RESULTS Two pancreatic cancer cell lines (PANC-1 and BxPC-3) were treated with gemcitabine, aspirin, and a combination (gemcitabine + aspirin). We found that the addition of aspirin enhanced the inhibitory effect of gemcitabine on the activity of PANC-1 and BxPC-3 cells. Quantitative N-glycoproteome, proteome, phosphorylation, and transcriptome data were obtained from integrated multi-omics analysis to evaluate the anti-tumor effects of aspirin and gemcitabine on pancreatic cancer cells. Mfuzz analysis of intact N-glycopeptide profiles revealed two consistent trends associated with the addition of aspirin, which showed a strong relationship between N-glycosylation and the synergistic effect of aspirin. Further analysis demonstrated that the dynamic regulation of sialylation and high-mannose glycoforms on ECM-related proteins (LAMP1, LAMP2, ITGA3, etc.) was a significant factor for the ability of aspirin to promote the anti-tumor activity of gemcitabine and the drug resistance of pancreatic cancer cells. CONCLUSIONS In-depth analysis of N-glycosylation-related processes and pathways in pancreatic cancer cells can provide new insight for future studies regarding pancreatic cancer therapeutic targets and drug resistance mechanisms.
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Affiliation(s)
- Xiaoyu Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, No. 38 Life Park Road, Changping District, Beijing, 102206, China
- Institute of Analysis and Testing, Beijing Center for Physical & Chemical Analysis), Beijing Academy of Science and Technology, Beijing, 100094, China
| | - Ran Kong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, No. 38 Life Park Road, Changping District, Beijing, 102206, China
- Biomedical Engineering Department, Peking University, Beijing, 100191, China
| | - Wenhao Hou
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, No. 38 Life Park Road, Changping District, Beijing, 102206, China
| | - Junxia Cao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, No. 38 Life Park Road, Changping District, Beijing, 102206, China
| | - Li Zhang
- Center for Bioinformatics and Computational Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
| | - Xiaohong Qian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, No. 38 Life Park Road, Changping District, Beijing, 102206, China
| | - Lijiao Zhao
- Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, No. 100 Ping Le Yuan, Chaoyang District, Beijing, 100124, China.
| | - Wantao Ying
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, No. 38 Life Park Road, Changping District, Beijing, 102206, China.
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30
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Su C, Mo J, Dong S, Liao Z, Zhang B, Zhu P. Integrinβ-1 in disorders and cancers: molecular mechanisms and therapeutic targets. Cell Commun Signal 2024; 22:71. [PMID: 38279122 PMCID: PMC10811905 DOI: 10.1186/s12964-023-01338-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 09/27/2023] [Indexed: 01/28/2024] Open
Abstract
Integrinβ-1 (ITGB1) is a crucial member of the transmembrane glycoprotein signaling receptor family and is also central to the integrin family. It forms heterodimers with other ligands, participates in intracellular signaling and controls a variety of cellular processes, such as angiogenesis and the growth of neurons; because of its role in bidirectional signaling regulation both inside and outside the membrane, ITGB1 must interact with a multitude of substances, so a variety of interfering factors can affect ITGB1 and lead to changes in its function. Over the past 20 years, many studies have confirmed a clear causal relationship between ITGB1 dysregulation and cancer development and progression in a wide range of benign diseases and solid tumor types, which may imply that ITGB1 is a prognostic biomarker and a therapeutic target for cancer treatment that warrants further investigation. This review summarizes the biological roles of ITGB1 in benign diseases and cancers, and compiles the current status of ITGB1 function and therapy in various aspects of tumorigenesis and progression. Finally, future research directions and application prospects of ITGB1 are suggested. Video Abstract.
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Affiliation(s)
- Chen Su
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China
| | - Jie Mo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China
| | - Shuilin Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China.
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, People's Republic of China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China.
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Chen B, Yu P, Chan WN, Xie F, Zhang Y, Liang L, Leung KT, Lo KW, Yu J, Tse GMK, Kang W, To KF. Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets. Signal Transduct Target Ther 2024; 9:6. [PMID: 38169461 PMCID: PMC10761908 DOI: 10.1038/s41392-023-01679-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 09/15/2023] [Accepted: 10/10/2023] [Indexed: 01/05/2024] Open
Abstract
Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc's involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc's cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.
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Affiliation(s)
- Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Peiyao Yu
- Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Wai Nok Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Fuda Xie
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Yigan Zhang
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Li Liang
- Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Kam Tong Leung
- Department of Pediatrics, The Chinese University of Hong Kong, Hong Kong, China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Gary M K Tse
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
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Fan J, Zhang Z, Chen H, Chen D, Yuan W, Li J, Zeng Y, Zhou S, Zhang S, Zhang G, Xiong J, Zhou L, Xu J, Liu W, Xu Y. Zinc finger protein 831 promotes apoptosis and enhances chemosensitivity in breast cancer by acting as a novel transcriptional repressor targeting the STAT3/Bcl2 signaling pathway. Genes Dis 2024; 11:430-448. [PMID: 37588209 PMCID: PMC10425751 DOI: 10.1016/j.gendis.2022.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 11/18/2022] [Accepted: 11/27/2022] [Indexed: 12/30/2022] Open
Abstract
Emerging evidence suggested that zinc finger protein 831 (ZNF831) was associated with immune activity and stem cell regulation in breast cancer. Whereas, the roles and molecular mechanisms of ZNF831 in oncogenesis remain unclear. ZNF831 expression was significantly diminished in breast cancer which was associated with promoter CpG methylation but not mutation. Ectopic over-expression of ZNF831 suppressed breast cancer cell proliferation and colony formation and promoted apoptosis in vitro, while knockdown of ZNF831 resulted in an opposite phenotype. Anti-proliferation effect of ZNF831 was verified in vivo. Bioinformatic analysis of public databases and transcriptome sequencing both showed that ZNF831 could enhance apoptosis through transcriptional regulation of the JAK/STAT pathway. ChIP and luciferase report assays demonstrated that ZNF831 could directly bind to one specific region of STAT3 promoter and induce the transcriptional inhibition of STAT3. As a result, the attenuation of STAT3 led to a restraint of the transcription of Bcl2 and thus accelerated the apoptotic progression. Augmentation of STAT3 diminished the apoptosis-promoting effect of ZNF831 in breast cancer cell lines. Furthermore, ZNF831 could ameliorate the anti-proliferation effect of capecitabine and gemcitabine in breast cancer cell lines. Our findings demonstrate for the first time that ZNF831 is a novel transcriptional suppressor through inhibiting the expression of STAT3/Bcl2 and promoting the apoptosis process in breast cancer, suggesting ZNF831 as a novel biomarker and potential therapeutic target for breast cancer patients.
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Affiliation(s)
- Jun Fan
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Zhe Zhang
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Hongqiang Chen
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Dongjiao Chen
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- Anesthesia and Intensive Care, Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Wenbo Yuan
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- School of Public Health, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jingzhi Li
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- School of Public Health, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Yong Zeng
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Shimeng Zhou
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Shu Zhang
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Gang Zhang
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Jiashen Xiong
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Lu Zhou
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Jing Xu
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Wenbin Liu
- Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Yan Xu
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
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Zhao Z, Wu Y, Liang X, Liu J, Luo Y, Zhang Y, Li T, Liu C, Luo X, Chen J, Wang Y, Wang S, Wu T, Zhang S, Yang D, Li W, Yan J, Ke Z, Luo F. Sonodynamic Therapy of NRP2 Monoclonal Antibody-Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy-Dependent Ferroptosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303872. [PMID: 37661565 PMCID: PMC10602529 DOI: 10.1002/advs.202303872] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/24/2023] [Indexed: 09/05/2023]
Abstract
The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development of innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron-based metal organic framework (Fe-MOF) nanocages encased in a covalent organic framework (COF) and modified with the pancreatic cancer-specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release the sonosensitizer sinoporphyrin sodium (DVDMS) and chemotherapeutic gemcitabine (GEM) and simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This system can overcome gemcitabine resistance in pancreatic cancer and reduce its toxicity to non-targeted cells and tissues. In a mechanistic cascade, the release of ROS activates the mitochondrial transition pore (MPTP), leading to the release of Ca2+ and induction of endoplasmic reticulum (ER) stress. Therefore, microtubule-associated protein 1A/1B-light chain 3 (LC3) is activated, promoting lysosomal autophagy. This process also induces autophagy-dependent ferroptosis, aided by the upregulation of Nuclear Receptor Coactivator 4 (NCOA4). This mechanism increases the sensitivity of pancreatic cancer cells to chemotherapeutic drugs and increases mitochondrial and DNA damage. The findings demonstrate the potential of GDMCN2 nanocages as a new avenue for the development of cancer therapeutics.
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Affiliation(s)
- Zhiyu Zhao
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Yanjie Wu
- School of Science and EngineeringShenzhen Key Laboratory of Innovative Drug SynthesisThe Chinese University of Hong KongShenzhen518172P.R. China
| | - Xiaochen Liang
- Environmental ToxicologyUniversity of CaliforniaRiversideCalifornia92507USA
| | - Jiajing Liu
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Yi Luo
- School of Basic MedicineSchool of Clinical MedicineFujian Medical UniversityFuzhou350122P.R. China
| | - Yijia Zhang
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Tingting Li
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Cong Liu
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Xian Luo
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Jialin Chen
- School of Basic MedicineSchool of Clinical MedicineFujian Medical UniversityFuzhou350122P.R. China
| | - Yunjie Wang
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Shengyu Wang
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Ting Wu
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Shaoliang Zhang
- Shanghai Guangsheng Biopharmaceutical Co., LtdShanghai200120P.R. China
| | - Dong Yang
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Wengang Li
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Jianghua Yan
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
| | - Zhihai Ke
- School of Science and EngineeringShenzhen Key Laboratory of Innovative Drug SynthesisThe Chinese University of Hong KongShenzhen518172P.R. China
| | - Fanghong Luo
- Cancer Research CenterSchool of MedicineXiamen UniversityXiamen361000P.R. China
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Xu X, Hou D, Wang Y, Zhang J, Hei Y, Wang B, Tian S, Zhang Y, Wang F. Knockdown of NF-κB activating protein promotes pancreatic cancer growth and metastasis through mTOR signaling pathway. Mol Biol Rep 2023; 50:7501-7513. [PMID: 37486443 DOI: 10.1007/s11033-023-08665-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/03/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND NF-κB activating protein (NKAP) acts as a transcriptional suppressor in the Notch signaling pathway, It plays a role in hematopoiesis maintenance, immune cell development, maturation, and functional competency acquisition. NKAP has been found to act as an oncogene in many tumors, but it has not been reported in PAAD.The purpose of this study was to investigate the effect of NKAP on the growth and metastasis of pancreatic adenocarcinoma(PAAD). METHODS AND RESULTS In this study, western blot and qRT-PCR showed that highly expressed NKAP was found in PAAD cell lines, and small interfering RNA (siRNA) was employed to reduce the expression of NKAP in PAAD cell lines. The results of CCK-8, clony formation, Transwell and flow cytometry showed that knockdown of NKAP significantly inhibited biological function of PAAD cells, and increased cell apoptosis. Study also observed that knockdown of NKAP inhibited the expression levels of apoptosis proteins and cyclin in PAAD cells. In addition, mTOR's degree of phosphorylation and the expression of its downstream target p70S6K can both be activated by NKAP. This effect was also confirmed in salvage experiments performed with Rapamycin(RaPa), an inhibitor of mTOR. At the end of the experiment, It was investigated how NKAP affected the drug sensitivity of gemcitabine used to treat PAAD. The results showed that knocking down NKAP could increase the drug sensitivity of gemcitabine. CONCLUSIONS NKAP as an oncogene regulates the development of PAAD cells. The research found that the mTOR signaling pathway is engaged in the oncogenic role of NKAP in PAAD for the first time.
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Affiliation(s)
- Xiangrong Xu
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Danyang Hou
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Yujie Wang
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Jing Zhang
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Yu Hei
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Bobo Wang
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Shuyue Tian
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China
| | - Yunqing Zhang
- Laboratory of Obstetrics and Gynecology, Affiliated Hospital of Yan'an University, Yan'an, Shaanxi Province, 716000, China
| | - Fenghui Wang
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, People's Republic of China.
- Yan'an Key Laboratory of Fungal Resources Development and Biological Control, Yan'an, Shaanxi Province, 716000, China.
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Sekiya S, Fukuda J, Yamamura R, Ooshio T, Satoh Y, Kosuge S, Sato R, Hatanaka KC, Hatanaka Y, Mitsuhashi T, Nakamura T, Matsuno Y, Hirano S, Sonoshita M. Drosophila Screening Identifies Dual Inhibition of MEK and AURKB as an Effective Therapy for Pancreatic Ductal Adenocarcinoma. Cancer Res 2023; 83:2704-2715. [PMID: 37378549 DOI: 10.1158/0008-5472.can-22-3762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/20/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023]
Abstract
Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The '4-hit' flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC. SIGNIFICANCE Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.
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Affiliation(s)
- Sho Sekiya
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Junki Fukuda
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Ryodai Yamamura
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Takako Ooshio
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Yusuke Satoh
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Shinya Kosuge
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Reo Sato
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Kanako C Hatanaka
- Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Yutaka Hatanaka
- Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Yoshihiro Matsuno
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Masahiro Sonoshita
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
- Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Sapporo, Japan
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Xu Y, Luan G, Liu F, Zhang Y, Li Z, Liu Z, Yang T. Exosomal miR-200b-3p induce macrophage polarization by regulating transcriptional repressor ZEB1 in hepatocellular carcinoma. Hepatol Int 2023; 17:889-903. [PMID: 36930410 DOI: 10.1007/s12072-023-10507-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/23/2023] [Indexed: 03/18/2023]
Abstract
PURPOSE Accumulating evidence has elucidated that the interaction between cancer cells and M2 macrophages plays an important role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the mechanism connecting tumor-derived exosomes, M2 polarization of macrophages, and liver metastasis remain unclear. Therefore, it is necessary to explore their influence on the tumor microenvironment of HCC. METHODS Transmission electron microscopy, nanometer particle testing, and special biomarker analysis were utilized to characterize exosomes, while the differential expression of microRNAs was evaluated using high-throughput sequencing technology. The functions of miR-200b-3p exosomes were confirmed using in vitro and in vivo assays. The interactions between microRNAs and ZEB1 as well as cancer cells and macrophages were measured using RNA pull-down and luciferase gene reporter assays. RESULTS Using in silico analysis, we identified high levels of miR-200b-3p exosome expression in patients with HCC, particularly with relapsed HCC. We demonstrated that HCC cell-derived miR-200b-3p exosomes were internalized by M0 macrophages and induced M2 polarization by downregulating ZEB1 and upregulating interleukin-4. As a result, the JAK/STAT signaling pathway was activated in M2 macrophages, leading to increased PIM1 and VEGFα expression. These cell factors accelerated the proliferation and metastasis of HCC, resulting in a feedback loop between HCC cells and M2 macrophages. CONCLUSION The study illustrates that HCC cell-derived miR-200b-3p exosomes facilitate the proliferation and polarization of macrophages by modulating cytokine secretion and the JAK/STAT signaling pathway, leading to the metastasis of HCC. These findings demonstrate the existence of a novel feedback loop between cancer cells and immune cells in the tumor microenvironment, presenting a new concept in cancer research.
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Affiliation(s)
- Ying Xu
- Shandong Cancer Hospital and Institute, Shandong Fist Medical University and Shandong Academy of Medical Science, No 440, Jiyan Road, Ji'nan, Shandong, China.
| | | | - Feng Liu
- The First Affiliated Hospital of Shandong First Medical University, Shandong, China
| | - Yuhua Zhang
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Zhongchao Li
- Shandong Cancer Hospital and Institute, Shandong Fist Medical University and Shandong Academy of Medical Science, No 440, Jiyan Road, Ji'nan, Shandong, China
| | - Ziming Liu
- Shandong Fist Medical University and Shandong Academy of Medical Science, Shandong, China
| | - Tao Yang
- Binzhou Medical University Hospital, Shandong, China
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Tanaka Y, Kamimura K, Shibata O, Ogawa K, Oda C, Abe H, Ikarashi S, Hayashi K, Yokoo T, Wakai T, Terai S. Similarity of oncogenic protein expression in KRAS G12D gene delivery-based rat pancreatic cancer model to that of human pancreatic cancer. Biochem Biophys Res Commun 2023; 673:29-35. [PMID: 37356142 DOI: 10.1016/j.bbrc.2023.06.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 05/20/2023] [Accepted: 06/16/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND The development of effective therapies and biomarkers for pancreatic cancer is an unmet clinical need. To address this, we have developed an easy-to-use pancreatic cancer rat animal model via pancreas-targeted hydrodynamic gene delivery of human pancreatic cancer-related genes. Our study aimed to determine the molecular similarity between the pancreatic tumor in the rat model and human pancreatic cancer. METHODS KRASG12D gene-expressing plasmid was delivered to the pancreas of wild type rats via pancreas-targeted hydrodynamic gene delivery as previously reported. Tissue samples were collected at 5 weeks after the first gene delivery. The tumors developed in the rats were assessed for the expression of oncogenic proteins that are involved in human pancreatic cancer development. RESULTS The development of a tumor mimicking pancreatic ductal adenocarcinoma was confirmed. The expression levels of Cyclin D1, c-Jun, IL-33, and Zip4 proteins in the tumor were immunohistochemically assessed and the correlation of the proteins was confirmed. The expression pattern showed similarity to that of surgically resected human pancreatic cancer tissues. CONCLUSIONS Our study findings showing a similar pattern of oncogenic protein expression in novel KRASG12D gene-induced rat pancreatic cancer model and human pancreatic cancer will be useful for establishing novel tumor markers and therapeutic options for pancreatic cancer.
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Affiliation(s)
- Yuto Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan; Department of General Medicine, Niigata University School of Medicine, Niigata, Niigata, 951-8510, Japan.
| | - Osamu Shibata
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Kohei Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Chiyumi Oda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Satoshi Ikarashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan
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Sui B, Chen J, Ge D, Liang F, Wang H. Assembly Characterization of Human Equilibrium Nucleoside Transporter 1 (hENT1) by Inhibitor Probe-Based dSTORM Imaging. Anal Chem 2023. [PMID: 37276019 DOI: 10.1021/acs.analchem.3c00596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Nucleoside transporters (NTs) play an important role in the metabolism of nucleoside substances and the efficacy of nucleoside drugs. Its spatial information related to biofunctions at the single-molecule level remains unclear, owing to the limitation of the existing labeling methods and traditional imaging methods. Therefore, we synthesize the inhibitor-based fluorescent probe SAENTA-Cy5 and apply direct stochastic optical reconstruction microscopy (dSTORM) to conduct refined observation of human equilibrative nucleoside transporter 1 (hENT1), the most important and famous member of NTs. We first demonstrate the labeling specificity and superiority of SAENTA-Cy5 to the antibody probe. Then, we found different assembly patterns of hENT1 on the apical and basal membranes, which are further investigated to be caused by varying associations of membrane carbohydrates, membrane classical functional domains (lipid rafts), and associated membrane proteins (EpCAM). Our work provides an efficient method for labeling hENT1, which contributes to realize fine observation of NTs. The findings on the assembly features and potential assembly mechanism of hENT1 promote a better understanding of its biofunction, which facilitates further investigations on how NTs work in the metabolism of nucleoside and nucleoside analogues.
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Affiliation(s)
- Binglin Sui
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei 430081, China
| | - Junling Chen
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei 430081, China
| | - Dian Ge
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei 430081, China
| | - Feng Liang
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei 430081, China
| | - Hongda Wang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Research Center of Biomembranomics, 5625 Renmin Street, Changchun, Jilin 130022, China
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Peng M, Ying Y, Zhang Z, Liu L, Wang W. Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy. Cancers (Basel) 2023; 15:cancers15092448. [PMID: 37173915 PMCID: PMC10177210 DOI: 10.3390/cancers15092448] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/09/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.
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Affiliation(s)
- Maozhen Peng
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ying Ying
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zheng Zhang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Qin P, Yan J, Huang H, Wang Q, Li M, Zhang Y, Wang J, Jiang T, Zhang X, Zhou Y. Equilibrative nucleoside transporter 3 promotes the progression of hepatocellular carcinoma by regulating the AKT/mTOR signaling pathway. Int J Biol Macromol 2023; 241:124323. [PMID: 37023875 DOI: 10.1016/j.ijbiomac.2023.124323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 03/18/2023] [Accepted: 03/31/2023] [Indexed: 04/08/2023]
Abstract
Equilibrative nucleoside transporter 3 (ENT3) belongs to the solute carrier family 29. Nucleoside transporters encoded by ENT3 play an important role in the uptake of nucleosides, nucleobases, and their nucleoside analogs, as well as participate in and regulate several physiological activities. However, no study has so far reported the role of ENT3 in hepatocellular carcinoma (HCC). We employed bioinformatics to analyze the expression, prognosis, and mechanism of ENT3 in HCC, as well as verified the same through biological experiments including cell proliferation, cell migration and invasion, and cell cycle and apoptosis, along with the detection of the AKT/mTOR protein expression in the pathway by Western blotting. ENT3 was widely and highly expressed in pan-cancer and upregulated in HCC. The upregulated ENT3 was related to the poor prognosis and clinical features in HCC patients. ENT3 knockdown inhibited cell proliferation, migration, and invasion and promoted cell apoptosis. ENT3 knockdown reduced the p-AKT and p-mTOR protein phosphorylation level, inhibited p-p70S6K1 and increased the p-4EBP1-the downstream effector of the AKT/mTOR pathway-protein phosphorylation level. Our study findings demonstrated that the expression of ENT3 was upregulated in HCC, which represents a poor prognosis. Thus, ENT3 promotes the progression of HCC through the AKT/mTOR signaling pathway.
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Affiliation(s)
- Peifang Qin
- Department of Microbiology, Guilin Medical University, Guilin 541004, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
| | - Jianguo Yan
- Department of Physiology, Guilin Medical University, Guilin 541004, China
| | - Haitao Huang
- Department of Microbiology, Guilin Medical University, Guilin 541004, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
| | - Qi Wang
- Department of Physiology, Guilin Medical University, Guilin 541004, China
| | - Mao Li
- Department of Physiology, Guilin Medical University, Guilin 541004, China
| | - Yuting Zhang
- Department of Microbiology, Guilin Medical University, Guilin 541004, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
| | - Jiahui Wang
- Department of Microbiology, Guilin Medical University, Guilin 541004, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
| | - Tingting Jiang
- Department of Microbiology, Guilin Medical University, Guilin 541004, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
| | - Xiaoling Zhang
- Department of Physiology, Guilin Medical University, Guilin 541004, China.
| | - Yali Zhou
- Department of Microbiology, Guilin Medical University, Guilin 541004, China; Institute of Pathogenic Biology, Guilin Medical University, Guilin 541004, China.
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Toledo B, González-Titos A, Hernández-Camarero P, Perán M. A Brief Review on Chemoresistance; Targeting Cancer Stem Cells as an Alternative Approach. Int J Mol Sci 2023; 24:ijms24054487. [PMID: 36901917 PMCID: PMC10003376 DOI: 10.3390/ijms24054487] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
The acquisition of resistance to traditional chemotherapy and the chemoresistant metastatic relapse of minimal residual disease both play a key role in the treatment failure and poor prognosis of cancer. Understanding how cancer cells overcome chemotherapy-induced cell death is critical to improve patient survival rate. Here, we briefly describe the technical approach directed at obtaining chemoresistant cell lines and we will focus on the main defense mechanisms against common chemotherapy triggers by tumor cells. Such as, the alteration of drug influx/efflux, the enhancement of drug metabolic neutralization, the improvement of DNA-repair mechanisms, the inhibition of apoptosis-related cell death, and the role of p53 and reactive oxygen species (ROS) levels in chemoresistance. Furthermore, we will focus on cancer stem cells (CSCs), the cell population that subsists after chemotherapy, increasing drug resistance by different processes such as epithelial-mesenchymal transition (EMT), an enhanced DNA repair machinery, and the capacity to avoid apoptosis mediated by BCL2 family proteins, such as BCL-XL, and the flexibility of their metabolism. Finally, we will review the latest approaches aimed at decreasing CSCs. Nevertheless, the development of long-term therapies to manage and control CSCs populations within the tumors is still necessary.
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Affiliation(s)
- Belén Toledo
- Department of Health Sciences, University of Jaén, Campus de las Lagunillas, 23071 Jaen, Spain
| | - Aitor González-Titos
- Department of Health Sciences, University of Jaén, Campus de las Lagunillas, 23071 Jaen, Spain
| | - Pablo Hernández-Camarero
- Department of Health Sciences, University of Jaén, Campus de las Lagunillas, 23071 Jaen, Spain
- Correspondence: (P.H.-C.); (M.P.)
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Campus de las Lagunillas, 23071 Jaen, Spain
- Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18016 Granada, Spain
- Biopathology and Regenerative Medicine, Institute (IBIMER), University of Granada, Centre for Biomedical Research (CIBM), 18071 Granada, Spain
- Correspondence: (P.H.-C.); (M.P.)
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microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15041230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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Periplocin exerts antitumor activity by regulating Nrf2-mediated signaling pathway in gemcitabine-resistant pancreatic cancer cells. Biomed Pharmacother 2023; 157:114039. [PMID: 36423542 DOI: 10.1016/j.biopha.2022.114039] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/17/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022] Open
Abstract
Although gemcitabine-based chemotherapy is common and effective for pancreatic cancer (PC), acquired drug resistance is one of the major reasons for treatment failure. Therefore, a novel therapeutic approach for gemcitabine-resistant PC is required. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oxidative stress-responsive transcription factor regulating antioxidant responses and plays a crucial role in chemoresistance. In the present study, the antitumor activity of periplocin, a natural cardiac glycoside, was evaluated in an established gemcitabine-resistant PC cell line (PANC-GR). Nrf2 was overexpressed in gemcitabine-resistant cells, and Nrf2 knockdown recovered gemcitabine sensitivity in PANC-GR cells. The antiproliferative activity of periplocin was highly associated with Nrf2 downregulation and Nrf2-mediated signaling pathways in PANC-GR cells. Periplocin also increased reactive oxygen species production inducing G0/G1 cell cycle arrest and apoptosis in PANC-GR cells. Periplocin and gemcitabine combined significantly inhibited tumor growth in a PANC-GR cells-implanted xenograft mouse model via Nrf2 downregulation. Overall, these findings suggest that periplocin might be a novel therapeutic agent against gemcitabine resistance, as it could recover sensitivity to gemcitabine by regulating Nrf2-mediated signaling pathways in gemcitabine-resistant PC cells.
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Zhou Z, Saluja AK, Houchen CW, Li M. Replication stress identifies novel molecular classification associated with treatment outcomes in pancreatic cancer. Pancreatology 2023; 23:82-89. [PMID: 36435734 DOI: 10.1016/j.pan.2022.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/17/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Replication stress is a prominent hallmark of tumor cells, which is crucial for maintaining genomic integrity. However, it remains poorly understood whether replication stress can serve as a surrogate biomarker to indicate prognosis and treatment response of pancreatic cancer. METHODS Transcriptomic and clinical data were obtained from The Cancer Genome Atlas and literature. An integrated signature of 18 replication-stress associated genes (termed as REST18) was established using the cox proportional hazards regression analysis. Tumors were sorted into REST18-low and REST18-high groups. Survival analysis, gene set enrichment analysis and composition of immune cells were compared between these tumors. RESULTS Patients with REST18-high tumors showed worse prognoses than those with REST18-low tumors in the TCGA database and the finding is validated in an independent cohort of pancreatic cancer. Comparison of REST18 model and other molecular classifications showed that REST18-high tumors are positively correlated to basal-like or squamous phenotypes, which have higher metastasis potential. DNA repair pathway is enriched in the REST18-high tumors. Analysis of tumor immune microenvironment found that REST18-high tumors are characterized with "immune-cold" features. Univariate and multivariate analysis show that REST18 is an independent risk factor for overall survival and predicts outcomes of chemotherapy in pancreatic cancer. CONCLUSION REST18 is a novel biomarker to indicate prognosis and treatment response of chemotherapy in pancreatic cancer.
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Affiliation(s)
- Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anuj K Saluja
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Courtney W Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| | - Min Li
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Wu J, Zhou Z, Li J, Liu H, Zhang H, Zhang J, Huang W, He Y, Zhu S, Huo M, Liu M, Zhang C. CHD4 promotes acquired chemoresistance and tumor progression by activating the MEK/ERK axis. Drug Resist Updat 2023; 66:100913. [PMID: 36603431 DOI: 10.1016/j.drup.2022.100913] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/13/2022] [Accepted: 12/22/2022] [Indexed: 12/27/2022]
Abstract
AIMS Chemoresistance remains a major challenge in gastric cancer (GC). Chromodomain helicase DNA-binding protein 4 (CHD4) mediated chromatin remodeling plays critical roles in various tumor types, but its role in chemoresistance in GC remains uncharacterized. METHODS CHD4 expression was examined by immunohistochemistry and Western blotting. The role of CHD4 on cell proliferation and chemoresistance of GC was examined in vitro and in vivo. Immunoprecipitation and liquid chromatography-mass spectrometry were used to identify CHD4-binding proteins and a proximity ligation assay was used to explore protein-protein interaction. RESULTS Chemoresistance is associated with upregulation of CHD4 in the tumor tissues of GC patients. Overexpression of CHD4 increased chemoresistance and cell proliferation. Knockdown of CHD4 induced cell apoptosis and cell cycle arrest. CHD4 mediates the decrease of the intracellular concentration of cisplatin by inducing drug efflux. Additionally, CHD4 promotes the interaction between ERK1/2 and MEK1/2, resulting in continuous activation of MEK/ERK pathway. Knockdown of CHD4 in GC increased sensitivity to chemotherapy and suppressed tumor growth in a mouse xenograft model. CONCLUSIONS This study identifies CHD4 dominated multi-drug efflux as a promising therapeutic target for overcoming acquired chemoresistance in GC.
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Affiliation(s)
- Jing Wu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, China
| | - Zhijun Zhou
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China
| | - Jin Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China
| | - Huifang Liu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China
| | - Huaqi Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China
| | - Junchang Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China
| | - Weibin Huang
- Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, China
| | - Shiyu Zhu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China
| | - Mingyu Huo
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China.
| | - Mingyang Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, Guangdong, China.
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Role of Up-Regulated Transmembrane Channel-Like Protein 5 in Pancreatic Adenocarcinoma. Dig Dis Sci 2022; 68:1894-1912. [PMID: 36459296 DOI: 10.1007/s10620-022-07771-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/14/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Pancreatic adenocarcinoma (PAAD) is a malignant tumor responsible for a heavy disease burden. Previously, only one pan-cancer study of Transmembrane channel-like protein 5 (TMC5) showed that TMC5 was highly expressed in PAAD, but the results lacked comprehensive verification, and the mechanism of TMC5 in PAAD was still unclear. METHODS For exploring the expression and clinical value of TMC5 in PAAD better, we adopted a comprehensive evaluation method, using internal immunohistochemistry (IHC) data combined with microarray and RNA-sequencing data collected from public databases. The single cell RNA-sequencing (scRNA-seq) data were exploited to explore the TMC5 expression in cell populations and intercellular communication. The potential mechanism of TMC5 in PAAD was analyzed from the aspects of immune infiltration, transcriptional regulation, function and pathway enrichment. RESULTS Our IHC data includes 148 PAAD samples and 19 non-PAAD samples, along with the available microarray and RNA-sequencing data (1166 PAAD samples, 704 non-PAAD samples). The comprehensive evaluation results showed that TMC5 was evidently up-regulated in PAAD (SMD = 1.17). Further analysis showed that TMC5 was over-expressed in cancerous epithelial cells. Furthermore, TMC5 was up-regulated in more advanced tumor T and N stages. Interestingly, we found that STAT3 as an immune marker of Th17 cells was not only positively correlated with TMC5 and up-regulated in PAAD tissues, but also the major predicted TMC5 transcription regulator. Moreover, STAT3 was involved in cancer pathway of PAAD. CONCLUSION Up-regulated TMC5 indicates advanced tumor stage in PAAD patients, and its role in promoting PAAD development may be regulated by STAT3.
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Zhu Z, Li W, Gong M, Wang L, Yue Y, Qian W, Zhou C, Duan W, Han L, Li L, Wu Z, Ma Q, Lin M, Wang S, Wang Z. Piezo1 act as a potential oncogene in pancreatic cancer progression. Life Sci 2022; 310:121035. [DOI: 10.1016/j.lfs.2022.121035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/26/2022] [Accepted: 09/30/2022] [Indexed: 11/06/2022]
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Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition. EBioMedicine 2022; 86:104352. [PMID: 36371988 PMCID: PMC9664470 DOI: 10.1016/j.ebiom.2022.104352] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/18/2022] [Accepted: 10/21/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. INTERPRETATION Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. FUNDING This study was supported by The National Natural Science Foundation of China.
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Li CY, Rajapakshe KI, Maitra A. Integrative transcriptomic analysis identifies a novel gene signature to predict prognosis of pancreatic cancer in different subtypes. Pancreatology 2022; 22:965-972. [PMID: 36008214 DOI: 10.1016/j.pan.2022.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent advances on pancreatic cancer molecular classifications have identified several subtypes with distinct characteristics, treatment response, and prognosis. We aim to identify the consensus gene signature that could predict the prognosis of pancreatic cancer. METHODS Transcriptomic data was acquired from TCGA database. Differentially expressed genes (DEGs) were identified by comparing the Basal-like, Quasi-mesenchymal and Squamous subtype to other subtypes. A new model was constructed by the least absolute shrinkage and selection operator to stratify patients into high and low-risk groups. The prognosis, transcriptomic profiles, and immune infiltration were examined between these groups. RESULTS We constructed a signature consisting of nine genes, and the GSEA analysis showed that the genomic profile of high-risk tumors is associated with the basal-like and squamous gene set enrichment. Patients with high-risk tumors had worse overall survival (P < 0.001) and progression free survival (P = 0.033), and are associated with a higher expression of KRAS downstream targets such as SDC1, ITGB4 and SLC2A1, which are involved in KRAS mediated macropinocytosis and tumor invasion. Meanwhile, several recurrence-associated genes increased in the high-risk tumors, including ITGA3 and TP63, which have been shown to mediate enhancer-dependent genomic reprogramming towards the squamous phenotype. The tumor immune infiltration profile analysis showed that high-risk tumors are characterized with an immune suppressive microenvironment. CONCLUSION The integrative transcriptomic analysis identifies a consensus gene signature that can discriminate pancreatic cancer subtypes and determine patient prognosis by evaluating the genomic reprogramming and the level of immune infiltration profile in pancreatic cancer.
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Affiliation(s)
- Cordelia Y Li
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kimal I Rajapakshe
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Anirban Maitra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Zhou Z, Ren Y, Yang J, Liu M, Shi X, Luo W, Fung KM, Xu C, Bronze MS, Zhang Y, Houchen CW, Li M. Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic Cancer. Gastroenterology 2022; 163:1281-1293.e1. [PMID: 35777482 PMCID: PMC9613512 DOI: 10.1053/j.gastro.2022.06.058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/09/2022] [Accepted: 06/17/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer. METHODS Clinical significance of ACSS2 was analyzed using samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein 9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. The macropinocytotic index was evaluated by dextran uptake assay. Chromatin immunoprecipitation assay was performed to validate transcriptional activation. ACSS2-mediated tumor progression and muscle wasting were examined in orthotopic xenograft models. RESULTS Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2-dimensional and 3-dimensional models. Macropinocytosis-associated genes are upregulated in tumor tissues and are correlated with worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified Zrt- and Irt-like protein 4 (ZIP4) as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2-induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4-mediated transcriptional activation. ZIP4 induces macropinocytosis through cyclic adenosine monophosphate response element-binding protein-activated syndecan 1 (SDC1) and dynamin 2 (DNM2). Meanwhile, ZIP4 drives muscle wasting and cachexia via glycogen synthase kinase-β (GSK3β)-mediated secretion of tumor necrosis factor superfamily member 10 (TRAIL or TNFSF10). ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models. CONCLUSIONS ACSS2-mediated metabolic reprogramming activates the ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through the GSK3β/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.
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Affiliation(s)
- Zhijun Zhou
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yu Ren
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Jingxuan Yang
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Mingyang Liu
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Xiuhui Shi
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wenyi Luo
- Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Kar-Ming Fung
- Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Chao Xu
- Department of Biostatistics and Epidemiology, Hudson College of Public Health, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Michael S Bronze
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yuqing Zhang
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Courtney W Houchen
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Min Li
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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