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Wang Y, Yang Z, Li Z, Huang L, Hou S, Wang J, Yu Y, Yin J, Wu J. Proteomics-driven discovery of LCAT as a novel biomarker for liver metastasis in colorectal cancer. BMC Cancer 2025; 25:480. [PMID: 40089671 PMCID: PMC11909834 DOI: 10.1186/s12885-025-13882-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/07/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND This study aimed to identify molecular markers that influence liver metastasis in colorectal cancer (CRC) and assess their clinical relevance. METHODS Proteomic analysis compared differential protein expression between CRC patients with liver metastasis (CRLM) and those without (CRNLM). Bioinformatics and survival analyses identified key proteins and validated them using the TCGA database for expression and clinical significance. Clinical and pathological data, along with tissue samples from our center, were used to create tissue microarrays for immunohistochemistry. Logistic regression assessed odds ratios (OR) for molecular markers linked to liver metastasis post-CRC surgery. Stable LCAT knockdown and overexpression CRC cell lines were constructed, and Transwell assays assessed the impact LCAT on cell migration. Nile red staining of these cells validated the effect LCAT on lipid metabolism in CRC cells. RESULTS Proteomic analysis identified 383 differentially expressed proteins between the CRLM and CRNLM groups (212 upregulated, 171 downregulated). Enrichment analysis linked these proteins to steroid and alcohol metabolism, inflammation, lipoproteins, and HDL particles, with key pathways in cholesterol and retinol metabolism. Lecithin cholesterol acyltransferase (LCAT), an important enzyme in this process, showed higher expression in CRC tissues, with increased LCAT linked to poorer 5-year OS, DSS, and PFI. LCAT expression also increased with tumor stage. Among 119 patients with CRC, preoperative complications, tumor staging, and LCAT scores differed significantly between patients with and without liver metastasis within 3 years post-surgery. LCAT and postoperative CEA levels were independent risk factors for liver metastasis (LCAT OR, 10.221; P = 0.002; CEA OR, 1.296; P = 0.014). Western blotting confirmed significantly higher LCAT expression in CRC tissues with liver metastasis. Transwell assays showed that LCAT overexpression enhanced migratory ability, while knockdown inhibited it. Nile red staining revealed increased lipid droplet accumulation in LCAT-overexpressing CRC cells, which was reduced by LCAT knockdown. CONCLUSION LCAT, which is involved in lipid metabolism, is an independent risk factor for liver metastasis following CRC surgery, suggesting its potential as a therapeutic target.
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Affiliation(s)
- Yuyao Wang
- Dalian Medical University, Dalian, China
- Department of Gastrointestinal Surgery, Chengdu Sixth People's Hospital, Chengdu, China
| | - Zhengbo Yang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China
| | - Ziqun Li
- Dalian Medical University, Dalian, China
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China
| | - Linglong Huang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China
| | - Shuangshuang Hou
- Department of Surgery, Fuyang Normal University Second Affiliated Hospital, Fuyang, China
| | - Jiaqi Wang
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China
| | - Yang Yu
- Dalian Medical University, Dalian, China
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China
| | - Jiajun Yin
- Dalian Medical University, Dalian, China.
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China.
| | - Ju Wu
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China.
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Ye C, Liu X, Liu Z, Pan C, Zhang X, Zhao Z, Sun H. Fusobacterium nucleatum in tumors: from tumorigenesis to tumor metastasis and tumor resistance. Cancer Biol Ther 2024; 25:2306676. [PMID: 38289287 PMCID: PMC10829845 DOI: 10.1080/15384047.2024.2306676] [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: 11/05/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024] Open
Abstract
Fusobacterium nucleatum, an anaerobic Gram-negative bacterium primarily residing in the oral cavity, has garnered significant attention for its emerging role in cancer progression and prognosis. While extensive research has revealed mechanistic links between Fusobacterium nucleatum and colorectal cancer, a comprehensive review spanning its presence and metastatic implications in cancers beyond colorectal origin is conspicuously absent. This paper broadens our perspective from colorectal cancer to various malignancies associated with Fusobacterium nucleatum, including oral, pancreatic, esophageal, breast, and gastric cancers. Our central focus is to unravel the mechanisms governing Fusobacterium nucleatum colonization, initiation, and promotion of metastasis across diverse cancer types. Additionally, we explore Fusobacterium nucleatum's adverse impacts on cancer therapies, particularly within the domains of immunotherapy and chemotherapy. Furthermore, this paper underscores the clinical research significance of Fusobacterium nucleatum as a potential tumor biomarker and therapeutic target, offering a novel outlook on its applicability in cancer detection and prognostic assessment.
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Affiliation(s)
- Chun Ye
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiao Liu
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zilun Liu
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Chuxuan Pan
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaowei Zhang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhanyi Zhao
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Laboratory Medicine, Central People’s Hospital of Ji’an, Shanghai East Hospital of Ji’an, Ji’an, China
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Wang J, Xu J, Liu X, Tong Y, Xu Z. Establishment of highly metastatic sublines and insights into telomerase expression during tumor metastasis using a microfluidic system. Talanta 2024; 280:126690. [PMID: 39126963 DOI: 10.1016/j.talanta.2024.126690] [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: 06/24/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
Metastasis is an important hallmark of malignant tumors, and telomerase often exhibits high expression in these tumors. Monitoring the real-time dynamics of telomerase will provide valuable insights into its association with tumor metastasis. In this study, we described a microfluidic system for screening highly metastatic sublines based on differential cell invasiveness, investigated telomerase expression in the process of tumor metastasis and explored the genes and signaling pathways involved in tumor metastasis. Cells with different metastasis abilities were efficiently classified into different channels, and the fluorescence imaging visually demonstrates that cells with higher metastasis ability have stronger telomerase activity. In addition, we successfully established the high-metastasis-ability LoVo subline (named as LoVo-H) and low-metastasis-ability LoVo subline (named as LoVo-L) from the human colorectal cancer LoVo cell lines through only one round of selection using the system. The results show that the LoVo-H cells display superior proliferation and invasiveness compared to LoVo-L cells. Furthermore, 6776 differentially expressed genes of LoVo-H compared with LoVo-L were identified by transcriptome sequencing. The genes associated with telomerase activity, cell migration and the epithelial to mesenchymal transition were up-regulated in LoVo-H, and PI3K-Akt signaling pathway, extracellular matrix-receptor interaction and Rap1 signaling pathway were significantly enriched in LoVo-H. This microfluidic system is a highly effective tool for selecting highly metastatic sublines and the LoVo-H subline established through this system presents a promising model for tumor metastasis research. Furthermore, this work preliminarily reveals telomerase expression during tumor metastasis and provides a new strategy for studying tumor metastasis and cancer diagnosis.
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Affiliation(s)
- Jie Wang
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Jiali Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Xiaopeng Liu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Yuxiao Tong
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Zhangrun Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China.
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Hsu YC, Luo CW, Chang SJ, Lai CY, Yang YT, Chen YZ, Liu WT, Wu CC, Sun CK, Hou MF, Pan MR. Targeting Bmi1 for Enhancing Anoikis Sensitivity and Inhibiting Metastasis in Colorectal Cancer. Cancer Genomics Proteomics 2024; 21:523-532. [PMID: 39191496 PMCID: PMC11363924 DOI: 10.21873/cgp.20469] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND/AIM Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario. MATERIALS AND METHODS We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis. RESULTS Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis. CONCLUSION Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC.
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Affiliation(s)
- Yin-Chou Hsu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Medicine for International Student, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Chi-Wen Luo
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C
- Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, R.O.C
| | - Shu-Jyuan Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Chiao-Ying Lai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Yu-Tzu Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Yi-Zi Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Wang-Ta Liu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Chun-Chieh Wu
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Cheuk-Kwan Sun
- School of Medicine for International Student, I-Shou University, Kaohsiung, Taiwan, R.O.C
- Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Ming-Feng Hou
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.;
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.;
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C
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Liu R, Li B, Zi J, Zhang R, Yu M, Zhou J, Pu Y, Xiong W. The dual role of LOXL4 in the pathogenesis and development of human malignant tumors: a narrative review. Transl Cancer Res 2024; 13:2026-2042. [PMID: 38737700 PMCID: PMC11082665 DOI: 10.21037/tcr-23-2003] [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: 10/29/2023] [Accepted: 02/16/2024] [Indexed: 05/14/2024]
Abstract
Background and Objective Lysyl oxidase-like protein 4 (LOXL4) is a secreted copper-dependent amine oxidase involved in the assembly and maintenance of extracellular matrix (ECM), playing a critical role in ECM formation and repair. Tumor-stroma interactions and ECM dysregulation are closely associated with the mechanisms underlying tumor initiation and progression. LOXL4 is the latest identified member of the lysyl oxidase (LOX) protein family. Currently, there is limited and controversial research on the role of LOXL4 in human malignancies. Its specific regulatory pathways, mechanisms, and roles in the occurrence, development, and treatment of malignancies remain incompletely understood. This article aims to illustrate the primary protein structure and the function of LOXL4 protein, and the relationship between LOXL4 protein and the occurrence and development of human malignant tumors to provide a reference for further clinical research. Methods We searched the English literature on LOXL4 in the occurrence and development of various malignant tumors in PubMed and Web of Science. The search keywords include "cancer" "LOXL4" "malignant tumor" "tumorigenesis and development", etc. Key Content and Findings LOXL4 is up-regulated in human gastric cancer, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, esophageal carcinoma and colorectal cancer, but down-regulated in human bladder cancer and lung cancer and inhibits tumor growth. There are two conflicting reports of both upregulation and downregulation in hepatocellular carcinoma, suggesting that LOXL4 has a bidirectional effect of promoting or inhibiting cancer in different types of human malignant tumors. We further explore the application prospect of LOXL4 protein in the study of malignant tumors, laying a theoretical foundation for the clinical diagnosis, treatment and screening of prognostic markers of malignant tumors. Conclusions LOXL4 exerts a bidirectional regulatory role, either inhibiting or promoting tumors depending on the type of cancer. We still need more research to further confirm the molecular mechanism of LOXL4 in cancer progression.
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Affiliation(s)
- Ruai Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
| | - Bin Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
| | - Jiaji Zi
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
| | - Ruopeng Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
| | - Min Yu
- Laboratory of Biochemistry and Molecular Biology, College of Life Sciences, Yunnan University, Kunming, China
| | - Jinghua Zhou
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
| | - Yuanqian Pu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
| | - Wei Xiong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dali University, Dali, China
- Key Laboratory of Clinical Biochemistry Test of Yunnan Province, College of Basic Medical Sciences, Dali University, Dali, China
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Wu J, Wang C, Cui X, Liu L, Wang L, Wang J, Xue X, Dang T. MicroRNA-128 acts as a suppressor in the progression of gastrointestinal stromal tumor by targeting B-lymphoma Mo-MLV insertion region 1. Clin Transl Oncol 2024; 26:363-374. [PMID: 38103120 DOI: 10.1007/s12094-023-03354-8] [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: 11/24/2022] [Accepted: 01/11/2023] [Indexed: 12/17/2023]
Abstract
INTRODUCTION The critical role of microRNA-128 (miR-128) in gastrointestinal-related diseases has been documented. In the current study, we tried to clarify the specific role miR-128 in gastrointestinal stromal tumor (GIST) and the underlying mechanism. METHODS Differentially expressed genes in GIST were identified following bioinformatics analysis. Then, expression patterns of miR-128 and B-lymphoma Mo-MLV insertion region 1 (BMI-1) in clinical tissue samples and cell lines were characterized, followed by validation of their correlation. GIST-T1 cells were selected and transfected with different mimic, inhibitor, or siRNA plasmids, after which the biological functions were assayed. RESULTS We identified low miR-128 and high BMI-1 expression in GIST tissues of 78 patients and 4 GIST cell lines. Ectopic expression of miR-128 or silencing of BMI-1 suppressed the malignant potentials of GIST-T1 cells. As a target of miR-128, BMI-1 re-expression could partly counteract the suppressive effect of miR-128 on the malignancy of GIST-T1 cells. CONCLUSION Our study provided evidence that miR-128-mediated silencing of BMI-1 could prevent malignant progression of GIST, highlighting a promising anti-tumor target for combating GIST.
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Affiliation(s)
- Jinbao Wu
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Changjuan Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Xia Cui
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Lin Liu
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Lu Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Jing Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Xiaohui Xue
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China.
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Wang R, Zhu F, Gao G, Gong Z, Yin Z, Ren W, Wang X, Liu Y, Wang S, Wu X. B-cell specific Moloney murine leukemia virus insertion site 1 contributes to invasion, metastasis, and poor prognosis in salivary adenoid cystic carcinoma. J Dent Sci 2024; 19:21-31. [PMID: 38303897 PMCID: PMC10829681 DOI: 10.1016/j.jds.2023.06.014] [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: 05/31/2023] [Revised: 06/13/2023] [Indexed: 02/03/2024] Open
Abstract
Background/purpose Upregulation of B-cell specific Moloney murine leukemia virus insertion site 1 (BMI-1) has been involved in the invasion, metastasis, and poor prognosis of many cancers. The aim of this study was to evaluate the levels and clinical significance of BMI-1 in saliva of patients with salivary adenoid cystic carcinoma (SACC), and to analyze biological function and mechanism of BMI-1 in the invasion and metastasis of SACC. Materials and methods The levels of BMI-1 in saliva and tumor tissues of SACC patients were determined. The correlation of salivary BMI-1 levels with clinicopathological parameters and clinical outcomes in patients with SACC was analyzed. Additionally, the effects of BMI-1 on wound-healing, transwell invasion, and epithelial-mesenchymal transition (EMT)-related protein expression in vitro as well as on tumorigenicity and experimental lung metastasis in vivo were investigated through exogenous overexpression and silencing of BMI-1 in SACC cells. Results BMI-1 levels increased in saliva and tumor tissues in SACC patients with invasion or metastasis. High salivary BMI-1 levels were correlated with poor TNM stage, poor overall survival, and disease-free survival. Exogenous expression of BMI-1 in SACC-83 promoted its migration and invasion, while silencing BMI-1 in SACC-LM inhibited its migration and invasion in vitro and suppressed tumorigenesis and lung metastasis in vivo. Furthermore, BMI-1 regulated the expression of EMT-related proteins in SACC. Conclusion Our study shows that BMI-1 can serve as a valuable biomarker to identify tumor invasion and metastasis in SACC, predict its prognosis, and act as a promising therapeutic target for SACC.
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Affiliation(s)
- Rongyan Wang
- Department of Stomatology, Affiliated Children's Hospital of Jiangnan University, Wuxi, China
| | - Fangyong Zhu
- Department of Stomatology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Guilin Gao
- Center of Stomatology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China
| | - Zhongjian Gong
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Zhiguo Yin
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Wei Ren
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Xin Wang
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yang Liu
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Shigang Wang
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Xiangbing Wu
- Department of Stomatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
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Cha BS, Jang YJ, Lee ES, Kim DY, Woo JS, Son J, Kim S, Shin J, Han J, Kim S, Park KS. Development of a Novel DNA Aptamer Targeting Colorectal Cancer Cell-Derived Small Extracellular Vesicles as a Potential Diagnostic and Therapeutic Agent. Adv Healthc Mater 2023; 12:e2300854. [PMID: 37129521 DOI: 10.1002/adhm.202300854] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/20/2023] [Indexed: 05/03/2023]
Abstract
Colorectal cancer (CRC) as the second leading cause of global cancer deaths poses critical challenges in clinical settings. Cancer-derived small extracellular vesicles (sEVs), which are secreted by cancer cells, have been shown to mediate tumor development, invasion, and even metastasis, and have thus received increasing attention for the development of cancer diagnostic or therapeutic platforms. In the present study, the sEV-targeted systematic evolution of ligands by exponential enrichment (E-SELEX) is developed to generate a high-quality aptamer (CCE-10F) that recognizes and binds to CRC-derived sEVs. Via an in-depth investigation, it is confirmed that this novel aptamer possesses high affinity (Kd = 3.41 nm) for CRC-derived sEVs and exhibits a wide linear range (2.0 × 104 -1.0 × 106 particles µL-1 ) with a limit of detection (LOD) of 1.0 × 103 particles µL-1 . Furthermore, the aptamer discriminates CRC cell-derived sEVs from those derived from normal colon cell, human serum, and other cancer cells, showing high specificity for CRC cell-derived sEVs and significantly suppresses the critical processes of metastasis, including cellular migration, invasion, and angiogenesis, which are originally induced by sEVs themselves. These findings are highly encouraging for the potential use of the aptamer in sEV-based diagnostic and therapeutic applications.
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Affiliation(s)
- Byung Seok Cha
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Young Jun Jang
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Eun Sung Lee
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Do Yeon Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Ji Su Woo
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jinseo Son
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Seokjoon Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jiye Shin
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jinjoo Han
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Seokhwan Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Ki Soo Park
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
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Ma N, Zhao S, Yang W, Wang Y. B-cell-specific Moloney murine leukemia virus integration site 1 knockdown impairs adriamycin resistance of gastric cancer cells. Arab J Gastroenterol 2023; 24:168-174. [PMID: 36878814 DOI: 10.1016/j.ajg.2023.02.004] [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: 04/13/2021] [Revised: 01/13/2023] [Accepted: 02/23/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND AND STUDY AIMS The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is associated with the progression of gastric cancer (GC). However, its role in drug resistance of gastric cancer stem cell (GCSC) remains unclear. This study aimed to explore the biological function of BMI-1 in GC cells and its role in drug resistance of GCSCs. PATIENTS AND METHODS We assessed BMI-1 expression in the GEPIA database and in our collected samples from patients with GC. We silenced BMI-1 using siRNA to study the cell proliferation and migration of GC cells. We also used Hoechst 33342 staining to verify the effect of adriamycin (ADR) on side population (SP) cells, and measured the effects of BMI-1 on the expression of N-cadherin, E-cadherin, and drug-resistance-related proteins (multidrug resistance mutation 1 and lung resistance-related protein). Finally, we analyzed BMI-1-related proteins uing the STRING and GEPIA databases. RESULTS BMI-1 mRNA was upregulated in GC tissues and cell lines, especially in MKN-45 and HGC-27 cells. Silencing BMI-1 reduced the proliferation and migration of GC cells. Knocking down BMI-1 significantly decreased epithelial-mesenchymal transition progression, expression levels of drug-resistant proteins, and the number of SP cells in ADR-treated GC cells. Bioinformatics analysis showed that EZH2, CBX8, CBX4, and SUZ12 were positively correlated with BMI-1 in GC tissues. CONCLUSION Our study demonstrates that BMI-1 affects the cellular activity, proliferation, migration, and invasion of GC cells. Silencing the BMI-1 gene significantly reduces the number of SP cells and the expression of drug-resistant proteins in ADR-treated GC cells. We speculate that inhibition of BMI-1 increases the drug resistance of GC cells by affecting GCSCs, and that EZH2, CBX8, CBX4, and SUZ12 may participate in BMI-1-induced enhancement of GCSC-like phenotype and viability.
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Affiliation(s)
- Ning Ma
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China.
| | - Sihui Zhao
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Wei Yang
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Yongfang Wang
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
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Jiang ZY, Ma XM, Luan XH, Liuyang ZY, Hong YY, Dai Y, Dong QH, Wang GY. BMI-1 activates hepatic stellate cells to promote the epithelial-mesenchymal transition of colorectal cancer cells. World J Gastroenterol 2023; 29:3606-3621. [PMID: 37398890 PMCID: PMC10311613 DOI: 10.3748/wjg.v29.i23.3606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/25/2023] [Accepted: 05/04/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Activated hepatic stellate cells (aHSCs) are the major source of cancer-associated fibroblasts in the liver. Although the crosstalk between aHSCs and colorectal cancer (CRC) cells supports liver metastasis (LM), the mechanisms are largely unknown.
AIM To explore the role of BMI-1, a polycomb group protein family member, which is highly expressed in LM, and the interaction between aHSCs and CRC cells in promoting CRC liver metastasis (CRLM).
METHODS Immunohistochemistry was carried out to examine BMI-1 expression in LM and matched liver specimens of CRC. The expression levels of BMI-1 in mouse liver during CRLM (0, 7, 14, 21, and 28 d) were detected by Western blotting (WB) and the quantitative polymerase chain reaction (qPCR) assay. We overexpressed BMI-1 in HSCs (LX2) by lentivirus infection and tested the molecular markers of aHSCs by WB, qPCR, and the immunofluorescence assay. CRC cells (HCT116 and DLD1) were cultured in HSC-conditioned medium (LX2 NC CM or LX2 BMI-1 CM). CM-induced CRC cell proliferation, migration, epithelial-mesenchymal transition (EMT) phenotype, and transforming growth factor beta (TGF-β)/SMAD pathway changes were investigated in vitro. A mouse subcutaneous xenotransplantation tumor model was established by co-implantation of HSCs (LX2 NC or LX2 BMI-1) and CRC cells to investigate the effects of HSCs on tumor growth and the EMT phenotype in vivo.
RESULTS Positive of BMI-1 expression in the liver of CRLM patients was 77.8%. The expression level of BMI-1 continued to increase during CRLM in mouse liver cells. LX2 overexpressed BMI-1 was activated, accompanied by increased expression level of alpha smooth muscle actin, fibronectin, TGF-β1, matrix metalloproteinases, and interleukin 6. CRC cells cultured in BMI-1 CM exhibited enhanced proliferation and migration ability, EMT phenotype and activation of the TGF-β/SMAD pathway. In addition, the TGF-βR inhibitor SB-505124 diminished the effect of BMI-1 CM on SMAD2/3 phosphorylation in CRC cells. Furthermore, BMI-1 overexpressed LX2 HSCs promoted tumor growth and the EMT phenotype in vivo.
CONCLUSION High expression of BMI-1 in liver cells is associated with CRLM progression. BMI-1 activates HSCs to secrete factors to form a prometastatic environment in the liver, and aHSCs promote proliferation, migration, and the EMT in CRC cells partially through the TGF-β/SMAD pathway.
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Affiliation(s)
- Zhong-Yang Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Xi-Mei Ma
- Department of Emergency, The Second Affiliated Hospital of Zhejing University, Hangzhou 310016, Zhejiang Province, China
| | - Xiao-Hui Luan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Zhen-Yu Liuyang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yi-Yang Hong
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yuan Dai
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Qing-Hua Dong
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310009, Zhejiang Province, China
| | - Guan-Yu Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
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Zhang W, Ou L, Peng C, Sang S, Feng Z, Zou Y, Yuan Y, Li H, Zhang G, Yao M. Sanguisorba officinalis L. enhances the 5-fluorouracil sensitivity and overcomes chemoresistance in 5-fluorouracil-resistant colorectal cancer cells via Ras/MEK/ERK and PI3K/Akt pathways. Heliyon 2023; 9:e16798. [PMID: 37484409 PMCID: PMC10360953 DOI: 10.1016/j.heliyon.2023.e16798] [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: 02/21/2023] [Revised: 05/17/2023] [Accepted: 05/29/2023] [Indexed: 07/25/2023] Open
Abstract
Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism. Materials and methods MTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells. Results These results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells. Conclusion In conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.
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Affiliation(s)
- Weijia Zhang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Ling Ou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Chang Peng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Shuyi Sang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Zhong Feng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
- International Pharmaceutical Engineering Lab, Shandong, 273400, China
| | - Yuanjing Zou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Yuemei Yuan
- School of Earth Sciences and Engineering, Sun Yat-sen University, Zhuhai, 519080, China
| | - Hao Li
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Guimin Zhang
- Lunan Pharmaceutical Group Co., Ltd, Linyi, 276000, Shandong, China
| | - Meicun Yao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
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Unraveling the function of epithelial-mesenchymal transition (EMT) in colorectal cancer: Metastasis, therapy response, and revisiting molecular pathways. Biomed Pharmacother 2023; 160:114395. [PMID: 36804124 DOI: 10.1016/j.biopha.2023.114395] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/03/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
Colorectal cancer (CRC) is a dangerous form of cancer that affects the gastrointestinal tract. It is a major global health concern, and the aggressive behavior of tumor cells makes it difficult to treat, leading to poor survival rates for patients. One major challenge in treating CRC is the metastasis, or spread, of the cancer, which is a major cause of death. In order to improve the prognosis for patients with CRC, it is necessary to focus on ways to inhibit the cancer's ability to invade and spread. Epithelial-mesenchymal transition (EMT) is a process that is linked to the spread of cancer cells, also known as metastasis. The process transforms epithelial cells into mesenchymal ones, increasing their mobility and ability to invade other tissues. This has been shown to be a key mechanism in the progression of colorectal cancer (CRC), a particularly aggressive form of gastrointestinal cancer. The activation of EMT leads to increases in the spread of CRC cells, and during this process, levels of the protein E-cadherin decrease while levels of N-cadherin and vimentin increase. EMT also contributes to the development of resistance to chemotherapy and radiation therapy in CRC. Non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a role in regulating EMT in CRC, often through their ability to "sponge" microRNAs. Anti-cancer agents have been shown to suppress EMT and reduce the progression and spread of CRC cells. These findings suggest that targeting EMT or related mechanisms may be a promising approach for treating CRC patients in the clinic.
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Jia F, Li Y, Gao Y, Wang X, Lu J, Cui X, Pan Z, Xu C, Deng X, Wu Y. Long-acting anti-colorectal cancer by nanocomplex co-regulating Bmi1 through miR-218 and siCCAT1. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
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Weidle UH, Nopora A. Up-regulated Circular RNAs in Colorectal Cancer: New Entities for Therapy and Tools for Identification of Therapeutic Targets. Cancer Genomics Proteomics 2023; 20:132-153. [PMID: 36870691 PMCID: PMC9989668 DOI: 10.21873/cgp.20369] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/20/2022] [Accepted: 12/28/2022] [Indexed: 03/06/2023] Open
Abstract
Patients with disseminated colorectal cancer have a dismal prognosis with a 5-year survival rate of only 13%. In order to identify new treatment modalities and new targets, we searched the literature for up-regulated circular RNAs in colorectal cancer which induce tumor growth in corresponding preclinical in vivo models. We identified nine circular RNAs that mediate resistance against chemotherapeutic agents, seven that up-regulate transmembrane receptors, five that induce secreted factors, nine that activate signaling components, five which up-regulate enzymes, six which activate actin-related proteins, six which induce transcription factors and two which up-regulate the MUSASHI family of RNA binding proteins. All of the circular RNAs discussed in this paper induce the corresponding targets by sponging microRNAs (miRs) and can be inhibited by RNAi or shRNA in vitro and in xenograft models. We have focused on circular RNAs with demonstrated activity in preclinical in vivo models because the latter is an important milestone in drug development. All circular RNAs with in vitro activity only data are not referenced in this review. The translational impact of inhibition of these circular RNAs and of the identified targets for treatment of colorectal cancer (CRC) are discussed.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Adam Nopora
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
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15
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Dong Y, Zhang K, Wei J, Ding Y, Wang X, Hou H, Wu J, Liu T, Wang B, Cao H. Gut microbiota-derived short-chain fatty acids regulate gastrointestinal tumor immunity: a novel therapeutic strategy? Front Immunol 2023; 14:1158200. [PMID: 37122756 PMCID: PMC10140337 DOI: 10.3389/fimmu.2023.1158200] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/17/2023] [Indexed: 05/02/2023] Open
Abstract
Tumor immune microenvironment (TIME), a tumor-derived immune component, is proven to be closely related to the development, metastasis, and recurrence of tumors. Gut microbiota and its fermented-metabolites short-chain fatty acids (SCFAs) play a critical role in maintaining the immune homeostasis of gastrointestinal tumors. Consisting mainly of acetate, propionate, and butyrate, SCFAs can interact with G protein-coupled receptors 43 of T helper 1 cell or restrain histone deacetylases (HDACs) of cytotoxic T lymphocytes to exert immunotherapy effects. Studies have shed light on SCFAs can mediate the differentiation and function of regulatory T cells, as well as cytokine production in TIME. Additionally, SCFAs can alter epigenetic modification of CD8+ T cells by inhibiting HDACs to participate in the immune response process. In gastrointestinal tumors, the abundance of SCFAs and their producing bacteria is significantly reduced. Direct supplementation of dietary fiber and probiotics, or fecal microbiota transplantation to change the structure of gut microbiota can both increase the level of SCFAs and inhibit tumor development. The mechanism by which SCFAs modulate the progression of gastrointestinal tumors has been elucidated in this review, aiming to provide prospects for the development of novel immunotherapeutic strategies.
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He H, Zhang S, Yang H, Xu P, Kutschick I, Pfeffer S, Britzen-Laurent N, Grützmann R, Fu D, Pilarsky C. Identification of Genes Associated with Liver Metastasis in Pancreatic Cancer Reveals PCSK6 as a Crucial Mediator. Cancers (Basel) 2022; 15:241. [PMID: 36612240 PMCID: PMC9818395 DOI: 10.3390/cancers15010241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Liver metastasis occurs frequently in patients with pancreatic cancer. We analyzed the molecular profiling in liver metastatic lesions aiming to uncover novel genes responsible for tumor progression. Bioinformatics analysis was applied to identify genes directing liver metastasis. CRISPR/Cas9 technology was used to knock out the candidate gene. Proliferation assays, colony formation assays, cell cycle analysis, migration assays, wound healing assays, Immunofluorescence analysis, and the tumor xenograft model of intrasplenic injection were adopted to evaluate the effects of PCSK6 inactivation on cell growth, migration and liver metastasis. GSEA and Western blot were used to investigate the corresponding signaling pathway. PCSK6 was one of the obtained liver-metastasis-related genes in pancreatic cancer. PCSK6 inactivation inhibited cell growth and cell migration, due to G0/G1 cell cycle arrest and the remodeling of cell-cell junctions or the cell skeleton, respectively. PCSK6 inactivation led to fewer counts and lower outgrowth rates of liver metastatic niches in vivo. The Raf-MEK1/2-ERK1/2 axis was repressed by PCSK6 inactivation. Accordingly, we found PCSK6 inactivation could inhibit cell growth, cell migration, and liver metastasis, and explored the role of the Raf-MEK1/2-ERK1/2 axis in PCSK6 inactivation. PCSK6-targeted therapy might represent a novel approach for combatting liver metastasis in pancreatic cancer.
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Affiliation(s)
- Hang He
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Shuman Zhang
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Hai Yang
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Pengyan Xu
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Isabella Kutschick
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Susanne Pfeffer
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Nathalie Britzen-Laurent
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Christian Pilarsky
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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Yang Y, Wu Z, Wang M, Wu Z, Sun Z, Liu M, Li G. MicroRNA-429 Regulates Invasion and Migration of Multiple Myeloma Cells via Bmi1/AKT Pathway. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Background: miR-429-mediated progression of multiple myeloma (MM) was studied through mediating B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1)/protein kinase B (AKT) pathway. Methods: miRNA or siRNA was delivered into MM cell lines to alter cellular
proliferation, apoptosis, invasion and migration. Measurements of miR-429 and Bmi1 levels were performed. AKT and p-AKT expression change was measured after regulating miR-429. The interaction between miR-429 and Bmi1 was analyzed. Results: miR-429 elevation disrupted proliferation,
anti-apoptosis, migration and invasion properties of MM cells, and inactivated AKT pathway. Bmi1 was a targeting partner of miR-429, which was highly expressed in MM. Bmi1 knockdown phenotyped the effects of overexpressed miR-429 on MM cells. AKT agonist SC70 reversed miR-429-regulated inhibition
of MM cell growth. Conclusion: miR-429 suppresses the activation of Bmi1/AKT pathway to down-regulate the malignant functions of MM cells.
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Affiliation(s)
- YongMing Yang
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
| | - ZhiFeng Wu
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
| | - Ming Wang
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
| | - ZuTong Wu
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
| | - ZhenZheng Sun
- Department of Pediatrics, The First Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
| | - Man Liu
- Department of Operating Room, The first Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
| | - GuangBao Li
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang College, ShaoYang City, HuNan Province, 422000, China
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曾 银, 樊 嵘. [PCGF1 is highly expressed in rectal adenocarcinoma and silencing PCGF1 inhibits proliferation of rectal adenocarcinoma cells in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1296-1302. [PMID: 36210701 PMCID: PMC9550553 DOI: 10.12122/j.issn.1673-4254.2022.09.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Indexed: 01/25/2023]
Abstract
OBJECTIVE To investigate the expression of PCGF1 in rectal adenocarcinoma (READ) and the effect of PCGF1 silencing on proliferation READ cells in vitro. METHODS The UALCAN and ENCORI online databases were used to analyze the expression level of PCGF1 in READ tissues and normal tissues and its association with the clinicopathological parameters and survival outcomes of patients with READ. The expression levels of PCGF1 were detected in two READ cell lines and a normal rectal epithelial cell line (HcoEpiC cells) using qPCR and Western blotting. Lentiviral vectors were used to construct PCGF1-overexpressing and PCGF1-silenced cell lines, and the proliferative activity of the cells was assessed using CCK-8 assay. The effect of PCGF1 silencing on tumor proliferation in vivo was also evaluated by observing tumorigenicity of the cells in nude mice. RESULTS PCGF1 was highly expressed in READ tissue (P < 0.001), and its expression levels was correlated with READ stage, differentiation and lymph node metastasis (P < 0.001). A high PCGF1 expression level was associated with a poor survival outcome of READ patients (P < 0.05). In SW837 and SW1463 cells, PCGF1 silencing significantly lowered the proliferative activity of the cells both in vitro (P < 0.05) and in nude mice (P < 0.01). CONCLUSION PCGF1 is highly expressed in READ tissue and may potentially serve as a prognostic biomarker as well as a therapeutic target for READ.
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Affiliation(s)
- 银珍 曾
- 南方医科大学南方医院麻醉科，广东 广州 510515Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 嵘 樊
- 天津市西青医院中心实验室，天津 300380Central Laboratory, Tianjin Xiqing Hospital, Tianjin 300380, China
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Sun W, Sun F, Meng J, Cao X, Zhao S, Wang C, Li L, Jiang P. Design, semi-synthesis and bioactivity evaluation of novel podophyllotoxin derivatives as potent anti-tumor agents. Bioorg Chem 2022; 126:105906. [DOI: 10.1016/j.bioorg.2022.105906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 11/02/2022]
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Singh T, Kaur P, Singh P, Singh S, Munshi A. Differential molecular mechanistic behavior of HDACs in cancer progression. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:171. [PMID: 35972597 DOI: 10.1007/s12032-022-01770-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/10/2022] [Indexed: 12/13/2022]
Abstract
Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs' role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.
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Affiliation(s)
- Tashvinder Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | - Prabhsimran Kaur
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India
| | | | - Sandeep Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India.
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India.
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Ye G, Huang M, Li Y, Ouyang J, Chen M, Wen Q, Li X, Zeng H, Long P, Fan Z, Yin J, Ye W, Zhang D. The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway. Acta Pharm Sin B 2022; 12:1288-1304. [PMID: 35530139 PMCID: PMC9072247 DOI: 10.1016/j.apsb.2021.08.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 01/02/2023] Open
Abstract
Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.
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22
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Wang R, Fan H, Sun M, Lv Z, Yi W. Roles of BMI1 in the Initiation, Progression, and Treatment of Hepatocellular Carcinoma. Technol Cancer Res Treat 2022; 21:15330338211070689. [PMID: 35072573 PMCID: PMC8793120 DOI: 10.1177/15330338211070689] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Liver cancer has high rates of morbidity and mortality, and its treatment is a global health challenge. Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancer cases. B-lymphoma Mo-MLV insertion region 1 (BMI1) has been identified as a proto-oncogene, which contributes to the initiation and progression of many malignant tumors. BMI1 expression is upregulated in HCC, and it influences the occurrence and development of HCC by various mechanisms, such as the INK4a/ARF locus, NF-κB signaling pathway, and PTEN/PI3K/AKT signaling pathway. In addition, the expression of BMI1 is related to prognosis and recurrence of HCC. Hence, there is clear evidence that BMI1 is a novel and valid therapeutic target for HCC. Accordingly, the development of therapeutic strategies targeting BMI1 has been a focus of recent research, providing new directions for HCC treatment. This review summarizes the role of BMI1 in the occurrence and treatment of HCC, which will provide a basis for using BMI1 as a potential target for the development of therapeutic strategies for HCC.
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Affiliation(s)
- Ru Wang
- 278245Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hengwei Fan
- 535219The Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, China
| | - Ming Sun
- 278245Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongwei Lv
- 278245Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wanwan Yi
- 278245Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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