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Lee GH, Kim YH, Woo SM, Lee WJ, Han SS, Park SJ, Price S, Tembo P, Hébert JR, Kim MK. The Impact of the Dietary Inflammatory Index, Fasting Blood Glucose, and Smoking Status on the Incidence and Survival of Pancreatic Cancer: A Retrospective Case-Control Study and a Prospective Study. Nutrients 2024; 16:3941. [PMID: 39599726 PMCID: PMC11597200 DOI: 10.3390/nu16223941] [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: 10/10/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Pancreatic cancer (PC), a highly malignant cancer with a poor diagnosis, may be influenced by diet-related inflammation. This study examined the association between dietary inflammatory index (DII) scores and the incidence and prognosis of PC in Korea. METHODS A total of 55 patients with PC were matched with 280 healthy controls (HCs) by age and sex. We also analyzed the combined effects of DII scores and fasting blood glucose (FBG) levels or smoking status on the risk of PC and performed a survival analysis using the Cox proportional hazards method. RESULTS The DII scores were higher in the patients with PC than those in HCs (odds ratio [OR] = 3.36, confidence interval [CI] = 1.16-9.73, p = 0.03), and the effect was larger in women (OR = 6.13, CI = 1.11-33.82, p = 0.04). A high DII score was jointly associated with FBG ≥ 126 mg/dL in raising PC risk [OR = 32.5, relative excess risk due to interaction/synergy (RERI/S) index = 24.2/4.34, p-interaction = 0.04], indicating a multiplicative interaction. A high DII score combined with ex/current smoker status increased PC risk through an additive interaction (RERI/S = 1.01/1.54, p-interaction = 0.76). However, DII scores did not influence disease-free survival. CONCLUSIONS The consumption of an anti-inflammatory diet, coupled with maintaining normal FBG levels and abstaining from smoking, may help reduce the risk of PC by mitigating pancreatic inflammation.
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Affiliation(s)
- Ga Hyun Lee
- Cancer Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (G.H.L.); (Y.H.K.)
| | - Yeon Hee Kim
- Cancer Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (G.H.L.); (Y.H.K.)
| | - Sang Myung Woo
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (S.M.W.); (W.J.L.); (S.-S.H.); (S.-J.P.)
| | - Woo Jin Lee
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (S.M.W.); (W.J.L.); (S.-S.H.); (S.-J.P.)
| | - Sung-Sik Han
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (S.M.W.); (W.J.L.); (S.-S.H.); (S.-J.P.)
| | - Sang-Jae Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (S.M.W.); (W.J.L.); (S.-S.H.); (S.-J.P.)
| | - Sherry Price
- Department of Epidemiology and Biostatistics and Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA; (S.P.); (P.T.); (J.R.H.)
| | - Penias Tembo
- Department of Epidemiology and Biostatistics and Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA; (S.P.); (P.T.); (J.R.H.)
| | - James R. Hébert
- Department of Epidemiology and Biostatistics and Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA; (S.P.); (P.T.); (J.R.H.)
- Department of Nutrition, Connecting Health Innovations LLC, Columbia, SC 29201, USA
| | - Mi Kyung Kim
- Cancer Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Ilsandong-gu, Goyang-si 10408, Republic of Korea; (G.H.L.); (Y.H.K.)
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Zohud O, Lone IM, Midlej K, Nashef A, Iraqi FA. Smad4 Heterozygous Knockout Effect on Pancreatic and Body Weight in F1 Population Using Collaborative Cross Lines. BIOLOGY 2024; 13:918. [PMID: 39596873 PMCID: PMC11592182 DOI: 10.3390/biology13110918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024]
Abstract
Smad4, a critical tumor suppressor gene, plays a significant role in pancreatic biology and tumorigenesis. Genetic background and sex are known to influence phenotypic outcomes, but their impact on pancreatic weight in Smad4-deficient mice remains unclear. This study investigates the impact of Smad4 deficiency on pancreatic weight in first-generation (F1) mice from diverse collaborative cross (CC) lines, focusing on the influence of genetic background and sex. F1 mice were generated by crossbreeding female CC mice with C57BL/6J-Smad4tm1Mak males. Genotyping confirmed the presence of Smad4 knockout alleles. Mice were housed under standard conditions, euthanized at 80 weeks, and their pancreatic weights were measured, adjusted for body weight, and analyzed for effects of Smad4 deficiency, sex, and genetic background. The overall population of F1 mice showed a slight but non-significant increase in adjusted pancreatic weights in heterozygous knockout mice compared to wild-type mice. Sex-specific analysis revealed no significant difference in males but a significant increase in adjusted pancreatic weights in heterozygous knockout females. Genetic background analysis showed that lines CC018 and CC025 substantially increased adjusted pancreatic weights in heterozygous knockout mice. In contrast, other lines showed no significant difference or varied non-significant changes. The interplay between genetic background and sex further influenced these outcomes. Smad4 deficiency affects pancreatic weight in a manner significantly modulated by genetic background and sex. This study highlights the necessity of considering these factors in genetic research and therapeutic development, demonstrating the value of the collaborative cross mouse population in dissecting complex genetic interactions.
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Affiliation(s)
- Osayd Zohud
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel Aviv 6997801, Israel; (O.Z.); (I.M.L.); (K.M.)
| | - Iqbal M. Lone
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel Aviv 6997801, Israel; (O.Z.); (I.M.L.); (K.M.)
| | - Kareem Midlej
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel Aviv 6997801, Israel; (O.Z.); (I.M.L.); (K.M.)
| | - Aysar Nashef
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya 1528001, Israel;
- Azrieli Faculty of Medicine, Bar-Ilan University, Ramat Gan 5290002, Israel
- Department of Oral and Maxillofacial Surgery, Meir Medical Center, Kfar Saba Affiliated to the Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel Aviv 6997801, Israel
| | - Fuad A. Iraqi
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel Aviv 6997801, Israel; (O.Z.); (I.M.L.); (K.M.)
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3
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Yao H, Luo L, Li R, Zhao Y, Zhang L, Pešić M, Cai L, Li L. New insight into the role of SMAD4 mutation/deficiency in the prognosis and therapeutic resistance of pancreatic ductal adenocarcinomas. Biochim Biophys Acta Rev Cancer 2024; 1879:189220. [PMID: 39571764 DOI: 10.1016/j.bbcan.2024.189220] [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: 05/19/2024] [Revised: 10/03/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) patients have an unfavorable prognosis and disappointing treatment outcomes because of late diagnosis, high chemotherapy resistance, ineffective adjuvant chemotherapy, unavailable molecular targeted therapy, and profound immunosuppressive effects in the tumor microenvironment (TME). There are a variety of critical driver proteins, such as KRAS, TP53, PTEN and SMAD4, putatively involved in PDAC etiology. Current knowledge of their molecular mechanisms is still limited. SMAD4 gene alterations in ∼55 % of patients emphasize its key role in PDAC progression, metastasis, resistance and immunity. Despite extensive studies on the TGF-β/SMAD pathway, the impact of SMAD4 mutation/deficiency on PDAC prognosis and treatment, especially its mechanism in drug resistance, has not yet been elucidated. This review summarizes the latest advances in the effect of SMAD4 deficiency on the prognosis and therapeutic resistance of PDAC patients. It might be a predictive and prognostic biomarker or therapeutic target to achieve the desired clinical benefits. Moreover, we discuss potential strategies to implement targeted therapies in terms of SMAD4 genetic status.
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Affiliation(s)
- Hongjuan Yao
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Liaoxin Luo
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China
| | - Rui Li
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Yelin Zhao
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Li Zhang
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China
| | - Milica Pešić
- Department of Neurobiology, Institute for Biological Research, "Siniša Stanković"- National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia
| | - Lin Cai
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China..
| | - Liang Li
- State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Biotechnology for Microbial Drugs; Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 1 Tiantan Xili, Beijing 100050, China.
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Li X, Wang Y, Cai L, Huang S. SMAD4 enhances the cytotoxic efficacy of human NK cells against colorectal cancer cells via the m 6A reader YTHDF2. Front Immunol 2024; 15:1440308. [PMID: 39439794 PMCID: PMC11494605 DOI: 10.3389/fimmu.2024.1440308] [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: 05/29/2024] [Accepted: 09/16/2024] [Indexed: 10/25/2024] Open
Abstract
Background Colorectal cancer (CRC) ranks as the third most prevalent malignant neoplasm in terms of both morbidity and mortality. Within the tumor microenvironment (TME) of CRC, the diminished presence and diminished cytotoxic function of natural killer (NK) cells serve as important factors driving the advancement of CRC; however, the precise regulatory mechanisms governing this phenomenon remain incompletely understood. Consequently, the identification of novel, potential anti-CRC targets associated with NK cells emerges as a pressing and paramount concern warranting immediate attention. Methods We examined the regulatory mechanism of SMAD4-mediated NK cell cytotoxicity on CRC by utilizing various experimental techniques, such as qRT-PCR, flow cytometry. Results Our findings revealed that the expression of SMAD4 is decreased in NK cells within the TME of human CRC. Furthermore, we observed that enforced upregulation of SMAD4 resulted in enhanced cytotoxicity of NK cells towards CRC cells. Furthermore, our research has revealed that YTHDF2 functions as a downstream effector of SMAD4, playing a crucial role in the control of transcription and translation of m6A-modified RNA. Moreover, our investigation demonstrated that increased expression of SMAD4 promoted the activating receptor NKG2D by elevating levels of YTHDF2. Ultimately, the SMAD4-YTHDF2 regulatory axis significantly enhanced the cytotoxicity of NK cells against human CRC cells. Conclusion Our study unveils a novel mechanism through which SMAD4 modulates the cytotoxicity of NK cells towards CRC cells, suggesting that SMAD4 may hold promise as a potential therapeutic target for NK cell therapy in CRC.
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Affiliation(s)
- Xinxin Li
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi’an, Shaanxi, China
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong, China
| | - Yilin Wang
- Department of Psychiatry, Zigong Mental Health Center, the Zigong Affiliated Hospital of Southwest Medical University, Zigong, Sichuan, China
| | - Lei Cai
- Division of Digestive Surgery, Hospital of Digestive Diseases, Xi’an International Medical Center, Xi’an, Shaanxi, China
| | - Siyong Huang
- Department of Hematology, Xi’an International Medical Center, Xi’an, Shaanxi, China
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Min J, Jiaqi H, Lihua L, Qianqian C, Shujuan W, Xiang L, Liang L, Liang R, Yiwu Z, Qian L. Proteomics of severe SARS-COV-2 infection and paraquat poisoning in human lung tissue samples: comparison of microbial infected and toxic pulmonary fibrosis. Front Cell Infect Microbiol 2024; 14:1446305. [PMID: 39301288 PMCID: PMC11410708 DOI: 10.3389/fcimb.2024.1446305] [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: 06/09/2024] [Accepted: 08/12/2024] [Indexed: 09/22/2024] Open
Abstract
Introduction Pulmonary fibrosis (PF) encompasses a spectrum of lung conditions characterized by the abnormal accumulation of scar tissue in the lungs, leading to impaired respiratory function. Various conditions can result in severe PF, among which viral infections have emerged as significant triggers. In addition to viral infections, exposure to toxic substances such as paraquat represents another significant risk factor for PF. Therefore, this study aimed to explore the dissimilarities and similarities between PF triggered by viral infections and chemical toxicants, using the mechanism of PF in IPF as a reference. Methods Data-independent acquisition proteomics technology was employed to identify COVID-19 and paraquat-induced PF from the autopsy of lung tissue samples obtained from individuals who died due to PF. Bioinformatics was employed for differential protein analysis, and selected indicators were validated on pathological sections. Results Our results showed that the differential proteins associated with the two causes of PF were enriched in similar lung fibrosis-related signaling pathways, such as the Wnt signaling pathway. However, differences were observed in proteins such as CACYBP, we verified the consistency of the results with proteomics using the IHC approach. Conclusion This study illuminates distinct protein-level differences by investigating pulmonary fibrosis pathways in severe COVID-19 and paraquat poisoning. Although both conditions activate lung-protective and repair pathways, COVID-19 shows limited phosphorylation-independent ubiquitination of β-catenin compared to paraquat toxicity. These findings shed light on potential therapeutic targets for PF induced via diverse factors.
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Affiliation(s)
- Jiang Min
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hou Jiaqi
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lin Lihua
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chai Qianqian
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wang Shujuan
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Xiang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Liang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ren Liang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhou Yiwu
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Qian
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Amani MS, Peymani M. Investigating the impact of SMAD2 and SMAD4 downregulation in colorectal cancer and their correlation with immune markers, prognosis, and drug resistance and sensitivity. Mol Biol Rep 2024; 51:831. [PMID: 39037563 DOI: 10.1007/s11033-024-09697-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: 04/11/2024] [Accepted: 06/03/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND While many genes linked to colorectal cancer (CRC) contribute to cancer development, a thorough investigation is needed to explore crucial hub genes yet to be fully studied. A pivotal pathway in CRC is transforming growth factor-beta (TGF-β). This study aimed to assess SMAD2 and SMAD4 gene expression from this pathway. METHODS AND RESULTS Counted data from the Cancer Genome Atlas (TCGA) were examined, comparing 483 tumor and 41 normal samples. Using clinical data, genes impacting overall survival (OS) were evaluated. GSE39582 was employed to confirmed the levels of genes in CRC compared to the normal samples. Additionally, employing unhealthy samples and the RT-qPCR means our outcomes was validated. Finally, PharmacoGx information were utilized to connect the levels of potential genes to drug tolerance and susceptibility. Our findings showed SMAD2 and SMAD4 levels in TGF-β signaling were more significant than other pathway genes. Our findings indicated that the protein levels of these genes were lower in malignant tissues than in healthy tissues. Results revealed a significant correlation between low levels of SMAD2 and unfavorable OS in CRC individuals. RT-qPCR results demonstrated decreased expressions of both SMAD2 and SMAD4 in cancer tissues compared to elevated levels in adjacent normal samples. Our results showed significant association between selected genes and immune cell infiltration markers such as CD8+, and B-cells. Our results indicated a potential association among the levels of SMAD2 and SMAD4 genes and tolerance and susceptibility to Nilotinib and Panobinostat drugs. CONCLUSION Reduced expression of SMAD2 and SMAD4 may be pivotal in CRC progression, impacting downstream genes unrelated to patient OS. These findings suggest a potential role for SMAD2 and SMAD4 as predictive markers for drug response in CRC patients.
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Affiliation(s)
- Melika Saadat Amani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
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Li K, Shu D, Li H, Lan A, Zhang W, Tan Z, Huang M, Tomasi ML, Jin A, Yu H, Shen M, Liu S. SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer. Cell Death Dis 2024; 15:444. [PMID: 38914552 PMCID: PMC11196642 DOI: 10.1038/s41419-024-06838-9] [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: 01/24/2024] [Revised: 06/11/2024] [Accepted: 06/14/2024] [Indexed: 06/26/2024]
Abstract
Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.
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MESH Headings
- Humans
- Smad4 Protein/metabolism
- Smad4 Protein/genetics
- Female
- Breast Neoplasms/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/drug therapy
- Signal Transduction/drug effects
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Receptor, ErbB-2/metabolism
- Receptor, ErbB-2/genetics
- Receptors, Estrogen/metabolism
- Cell Line, Tumor
- Animals
- Tamoxifen/pharmacology
- Tamoxifen/therapeutic use
- Tamoxifen/analogs & derivatives
- Mice
- Antineoplastic Agents, Hormonal/pharmacology
- Antineoplastic Agents, Hormonal/therapeutic use
- Mice, Nude
- Gene Expression Regulation, Neoplastic/drug effects
- Autophagy/drug effects
- ErbB Receptors/metabolism
- ErbB Receptors/genetics
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Affiliation(s)
- Kang Li
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Dan Shu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Han Li
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Ailin Lan
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Wenjie Zhang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Zhaofu Tan
- Department of Dermatology and Venereology, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Man Huang
- Department of Breast Center, Chongqing University Three Gorges Hospital, Wanzhou, 404000, Chongqing, China
| | - Maria Lauda Tomasi
- Department of Medicine, Cedars-Sinai Medical Center, DAVIS Research Building 3096A, 8700 Beverly Blv, Los Angeles, CA, 90048, USA
| | - Aishun Jin
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, 400010, Chongqing, China
| | - Haochen Yu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
| | - Meiying Shen
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
| | - Shengchun Liu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
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Li X, Wang Y, Wang X, Shen Y, Yuan Y, He Q, Mao S, Wu C, Zhou M. Downregulation of SMAD4 protects HaCaT cells against UVB-induced damage and oxidative stress through the activation of EMT. Photochem Photobiol Sci 2024; 23:1051-1065. [PMID: 38684635 DOI: 10.1007/s43630-024-00574-x] [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: 12/28/2023] [Accepted: 04/04/2024] [Indexed: 05/02/2024]
Abstract
As a member of the SMAD family, SMAD4 plays a crucial role in several cellular biological processes. However, its function in UVB radiation-induced keratinocyte damage is not yet clarified. Our study aims to provide mechanistic insight for the development of future UVB protective therapies and therapeutics involving SMAD4. HaCaT cells were treated with UVB, and the dose dependence and time dependence of UVB were measured. The cell function of UVB-treated HaCaT cells and the activity of epithelial-mesenchymal transition (EMT) after overexpression or silencing of SMAD4 was observed by flow cytometry, quantitative reverse transcription PCR (qRT-PCR) and Western Blots (WB). We found that a significant decrease in SMAD4 was observed in HaCaT cells induced by UVB. Our data confirm SMAD4 as a direct downstream target of miR-664. The down-regulation of SMAD4 preserved the viability of the UVB-treated HaCaT cells by inhibiting autophagy or apoptosis. Furthermore, the silencing of SMAD4 activated the EMT process in UVB-treated HaCaT cells. Down-regulation of SMAD4 plays a protective role in UVB-treated HaCaT cells via the activation of EMT.
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Affiliation(s)
- Xiangzhi Li
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
- Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou, 545000, China
- Taizhou Key Laboratory of Minimally Invasive Interventional Therapy & Artificial Intelligence, Taizhou Branch of Zhejiang Cancer Hospital (Taizhou Cancer Hospital), Taizhou, 317502, China
| | - Yimeng Wang
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
- Yancheng Center for Disease Control and Prevention, Yancheng, 224000, China
| | - Xian Wang
- Department of Public Health and Management, Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Yi Shen
- Department of Public Health and Management, Youjiang Medical University for Nationalities, Baise, 533000, China
| | - Yawen Yuan
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Qingquan He
- Taizhou Key Laboratory of Minimally Invasive Interventional Therapy & Artificial Intelligence, Taizhou Branch of Zhejiang Cancer Hospital (Taizhou Cancer Hospital), Taizhou, 317502, China
| | - Shuyi Mao
- Nuclear Medicine Department, The Second Affiliated Hospital of Guangxi University of Science and Technology, Liuzhou, 545006, China
| | - Cailian Wu
- Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou, 545000, China
| | - Meijuan Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China.
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Olaoba OT, Adelusi TI, Yang M, Maidens T, Kimchi ET, Staveley-O’Carroll KF, Li G. Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy. Cancers (Basel) 2024; 16:1808. [PMID: 38791887 PMCID: PMC11119842 DOI: 10.3390/cancers16101808] [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: 04/12/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.
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Affiliation(s)
- Olamide T. Olaoba
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Temitope I. Adelusi
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Ming Yang
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Tessa Maidens
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA;
| | - Eric T. Kimchi
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
| | - Guangfu Li
- Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; (O.T.O.); (T.I.A.); (M.Y.); (E.T.K.)
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Steinbach A, Kun J, Urbán P, Palkovics T, Polgár B, Schneider G. Molecular Responses of the Eukaryotic Cell Line INT407 on the Internalized Campylobacter jejuni-The Other Side of the Coin. Pathogens 2024; 13:386. [PMID: 38787238 PMCID: PMC11124400 DOI: 10.3390/pathogens13050386] [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] [Revised: 04/21/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
Campylobacter jejuni is a zoonotic bacterium with the capacity to invade the epithelial cells during the pathogenic process. Several bacterial factors have been identified to contribute to this process, but our knowledge is still very limited about the response of the host. To reveal the major routes of this response, a whole-transcriptome analysis (WTA) was performed where gene expressions were compared between the 1st and the 3rd hours of internalization in INT407 epithelial cells. From the 41,769 human genes tested, altogether, 19,060 genes were shown through WTA to be influenced to different extents. The genes and regulation factors of transcription (296/1052; 28%), signal transduction (215/1052; 21%), apoptosis (153/1052; 15%), immune responses (97/1052; 9%), transmembrane transport (64/1052; 6%), cell-cell signaling (32/1052; 3%), cell-cell adhesions (29/1052; 3%), and carbohydrate metabolism (28/1052; 3%) were the most affected biological functions. A striking feature of the gene expression of this stage of the internalization process is the activation of both immune functions and apoptosis, which convincingly outlines that the invaded cell faces a choice between death and survival. The seemingly balanced status quo between the invader and the host is the result of a complex process that also affects genes known to be associated with postinfectious pathological conditions. The upregulation of TLR3 (3.79×) and CD36 (2.73×), two general tumor markers, and SERPINEB9 (11.37×), FNDC1 (7.58×), and TACR2 (8.84×), three factors of tumorigenesis, confirms the wider pathological significance of this bacterium.
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Affiliation(s)
- Anita Steinbach
- Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 7624 Pécs, Hungary; (A.S.); (T.P.); (B.P.)
| | - József Kun
- Hungarian Centre for Genomics and Bioinformatics, Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary; (J.K.); (P.U.)
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Péter Urbán
- Hungarian Centre for Genomics and Bioinformatics, Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary; (J.K.); (P.U.)
| | - Tamás Palkovics
- Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 7624 Pécs, Hungary; (A.S.); (T.P.); (B.P.)
| | - Beáta Polgár
- Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 7624 Pécs, Hungary; (A.S.); (T.P.); (B.P.)
| | - György Schneider
- Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 7624 Pécs, Hungary; (A.S.); (T.P.); (B.P.)
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Chen Q, Guo H, Jiang H, Hu Z, Yang X, Yuan Z, Gao Y, Zhang G, Bai Y. S100A2 induces epithelial-mesenchymal transition and metastasis in pancreatic cancer by coordinating transforming growth factor β signaling in SMAD4-dependent manner. Cell Death Discov 2023; 9:356. [PMID: 37758734 PMCID: PMC10533899 DOI: 10.1038/s41420-023-01661-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/08/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor and is associated with a poor prognosis. Treatment strategies for PDAC are largely ineffective primarily because of delay in its diagnosis and limited efficacy of systematic treatment. S100A2 is associated with the proliferation, migration, and differentiation of several tumors; however, its effects on PDAC and the associated molecular mechanisms remain to be explored. We studied the mechanisms underlying the effect of S100A2 on epithelial-mesenchymal transition (EMT) and metastasis in PDAC cells. We found that the level of S100A2 remarkably increased and was associated with poor PDAC prognosis. The overexpression of S100A2 in PANC-1 cells also induced EMT, in addition to increasing the invasion and migration of PDAC cells, whereas the knockdown of S100A2 markedly inhibited cell metastasis. Furthermore, S100A2 was found to enhance metastatic abilities in vivo. The overexpression of S100A2 increased SMAD4 expression, whereas the knockdown of S100A2 reduced SMAD4 expression. SMAD4 overexpression could effectively rescue the effects of S100A2 knockdown on EMT. S100A2 mechanistically activated the transforming growth factor (TGF)-β/Smad2/3 signaling pathway, upregulated SMAD4 expression, induced EMT, and increased PANC-1 cell metastasis. In conclusion, the S100A2/SMAD4 axis modulates EMT to accelerate PDAC development. Our results supplement and enrich the understanding of the pathogenesis underlying PDAC and provide a new theoretical basis and strategy targeting S100A2 for the diagnosis and treatment of PDAC.
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Affiliation(s)
- Qinbo Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Hangcheng Guo
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Haojie Jiang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Zujian Hu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Xuejia Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Ziwei Yuan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Yuanyuan Gao
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China
| | - Ge Zhang
- Department of Orthopedics, The First Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Yongheng Bai
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China.
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China.
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Huang Y, Wu Z, Lan W, Zhong C. Predicting Disease-Associated N7-Methylguanosine (m 7G) Sites via Random Walk on Heterogeneous Network. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2023; 20:3173-3181. [PMID: 37294648 DOI: 10.1109/tcbb.2023.3284505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Recent studies revealed that the modification of N7-methylguanosine (m7G) has associations with many human diseases. Effectively identifying disease-associated m7G methylation sites would provide crucial clues for disease diagnosis and treatment. Previous studies have developed computational methods to predict disease-associated m7G sites based on similarities among m7G sites and diseases. However, few have focused on the influence of the known m7G-disease association information on calculating similarity measures of m7G site and disease, which potentially promotes the identification of the disease-associated m7G sites. In this work, we propose а computational method called m7GDP-RW to predict m7G-disease associations by random walk algorithm. m7GDP-RW first incorporates the feature information of m7G site and disease with the known m7G-disease associations to compute m7G site similarity and disease similarity. Then m7GDP-RW combines the known m7G-disease associations with the computed similarity of m7G site and disease to construct a m7G-disease heterogeneous network. Finally, m7GDP-RW utilizes a two-pass random walk with restart algorithm to find novel m7G-disease associations on the heterogeneous network. The experimental results show that our method achieves higher prediction accuracy compared to the existing methods. The study case also demonstrates the effectiveness of m7GDP-RW in discovering potential m7G-disease associations.
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Pourali G, Zafari N, Velayati M, Mehrabadi S, Maftooh M, Hassanian SM, Mobarhan MG, Ferns GA, Avan A, Khazaei M. Therapeutic Potential of Targeting Transforming Growth Factor-beta (TGF-β) and Programmed Death-ligand 1 (PD-L1) in Pancreatic Cancer. Curr Drug Targets 2023; 24:1335-1345. [PMID: 38053355 DOI: 10.2174/0113894501264450231129042256] [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: 07/01/2023] [Revised: 10/11/2023] [Accepted: 10/24/2023] [Indexed: 12/07/2023]
Abstract
Pancreatic cancer (PC) is one the most lethal malignancies worldwide affecting around half a million individuals each year. The treatment of PC is relatively difficult due to the difficulty in making an early diagnosis. Transforming growth factor-beta (TGF-β) is a multifunctional factor acting as both a tumor promoter in early cancer stages and a tumor suppressor in advanced disease. Programmed death-ligand 1 (PD-L1) is a ligand of programmed death-1 (PD-1), an immune checkpoint receptor, allowing tumor cells to avoid elimination by immune cells. Recently, targeting the TGF-β signaling and PD-L1 pathways has emerged as a strategy for cancer therapy. In this review, we have summarized the current knowledge regarding these pathways and their contribution to tumor development with a focus on PC. Moreover, we have reviewed the role of TGF-β and PD-L1 blockade in the treatment of various cancer types, including PC, and discussed the clinical trials evaluating TGF-β and PD-L1 antagonists in PC patients.
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Affiliation(s)
- Ghazaleh Pourali
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Doctor, Mashhad University of Medical Science, Mashhad, Iran
| | - Nima Zafari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahla Velayati
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Mehrabadi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Maftooh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Science, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Science, Mashhad, Iran
| | - Majid Ghayour Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Science, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Science, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Science, Mashhad, Iran
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Matsumura K, Hayashi H, Uemura N, Ogata Y, Zhao L, Sato H, Shiraishi Y, Kuroki H, Kitamura F, Kaida T, Higashi T, Nakagawa S, Mima K, Imai K, Yamashita YI, Baba H. Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-β signal activation in pancreatic ductal adenocarcinoma. Transl Oncol 2022; 26:101533. [PMID: 36115074 PMCID: PMC9483797 DOI: 10.1016/j.tranon.2022.101533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-β (TGF-β) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-β signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-β signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-β signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-β activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-β signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.
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Affiliation(s)
- Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yoko Ogata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Liu Zhao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideyuki Kuroki
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Fumimasa Kitamura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
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Guan S, Deng G, Sun J, Han Q, Lv Y, Xue T, Ding L, Yang T, Qian N, Dai G. Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma. Front Oncol 2022; 12:926260. [PMID: 36081557 PMCID: PMC9446234 DOI: 10.3389/fonc.2022.926260] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
PurposePancreatic cancer is an aggressive solid tumor with a severe prognosis. Although tumor biomarkers are often used to identify advanced pancreatic cancer, this is not accurate, and the currently used biomarkers are not indicative of prognosis. The present study evaluated circulating tumor DNA (ctDNA) as a biomarker for prognosis prediction and disease monitoring in metastatic pancreatic adenocarcinoma (PAC).MethodsFrom 2017 to 2018, 40 patients with metastatic PAC were enrolled, and tumor tissue and blood samples were collected from 40 and 35 patients, respectively. CtDNA was sequenced by next-generation sequencing (NGS) with a 425-gene capture panel. The association of clinical characteristics, laboratory indicators, and dynamic ctDNA with patient outcomes was analyzed.ResultsMutations in KRAS (87.5%, N = 35) and TP53 (77.5%, N = 31) were most common in 40 tumor tissue. Patients’ ECOG score, CA19-9, CEA, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) levels and mutations in ≥ 3 driver genes were strongly correlated with patients’ overall survival (OS). Patients’ gender, ECOG score, CA19-9, and CEA levels were associated with progression-free survival (PFS) (P<0.05). In 35 blood samples, univariate analysis showed a significant association between ECOG score, CA19-9, KRAS or CDKN2A mutation in ctDNA and OS and between CA19-9, CDKN2A or SMAD4 mutation in ctDNA and PFS. Cox hazard proportion model showed that patients’ CDKN2A mutation in ctDNA (HR=16.1, 95% CI=4.4-59.1, P<0.001), ECOG score (HR=6.2, 95% CI=2.4-15.7, P<0.001) and tumor location (HR=0.4, 95% CI=0.1-0.9, P=0.027) were significantly associated with OS. Patients’ CDKN2A mutation in ctDNA (HR=6.8, 95% CI=2.3-19.9, P=0.001), SMAD4 mutation in ctDNA (HR=3.0, 95% CI=1.1-7.9, P=0.031) and metastatic organ (HR=0.4, 95% CI=0.2-1.0, P=0.046) were significantly associated with PFS. Longitudinal changes in gene mutation allelic frequency (MAF) value were evaluated in 24 patients. Detection of progression disease (PD) by ctDNA was 0.9 months earlier than by radiological imaging (mean PFS: 4.6m vs 5.5m, P=0.004, paired t-test).ConclusionsThe ctDNA has the potential as a specific survival predictive marker for metastatic PAC patients. Longitudinal ctDNA tracking could potentially help identify disease progression and be a valuable complement for routine clinical markers and imaging.
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Affiliation(s)
- Shasha Guan
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Guochao Deng
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Jingjie Sun
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Quanli Han
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Yao Lv
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Tianhui Xue
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Lijuan Ding
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Tongxin Yang
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Niansong Qian
- Department of Thoracic Oncology, The Eighth Medical Center, Chinese People’ Liberation Army (PLA) General Hospital, Beijing, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- *Correspondence: Niansong Qian, ; Guanghai Dai,
| | - Guanghai Dai
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Niansong Qian, ; Guanghai Dai,
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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Wang HL, Wang L, Zhao CY, Lan HY. Role of TGF-Beta Signaling in Beta Cell Proliferation and Function in Diabetes. Biomolecules 2022; 12:373. [PMID: 35327565 PMCID: PMC8945211 DOI: 10.3390/biom12030373] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 12/27/2022] Open
Abstract
Beta (β) cell dysfunction or loss is the common pathological feature in all types of diabetes mellitus (diabetes). Resolving the underlying mechanism may facilitate the treatment of diabetes by preserving the β cell population and function. It is known that TGF-β signaling plays diverse roles in β cell development, function, proliferation, apoptosis, and dedifferentiation. Inhibition of TGF-β signaling expands β cell lineage in the development. However, deletion of Tgfbr1 has no influence on insulin demand-induced but abolishes inflammation-induced β cell proliferation. Among canonical TGF-β signaling, Smad3 but not Smad2 is the predominant repressor of β cell proliferation in response to systemic insulin demand. Deletion of Smad3 simultaneously improves β cell function, apoptosis, and systemic insulin resistance with the consequence of eliminated overt diabetes in diabetic mouse models, revealing Smad3 as a key mediator and ideal therapeutic target for type-2 diabetes. However, Smad7 shows controversial effects on β cell proliferation and glucose homeostasis in animal studies. On the other hand, overexpression of Tgfb1 prevents β cells from autoimmune destruction without influence on β cell function. All these findings reveal the diverse regulatory roles of TGF-β signaling in β cell biology.
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Affiliation(s)
- Hong-Lian Wang
- Research Center for Integrative Medicine, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (H.-L.W.); (L.W.)
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Li Wang
- Research Center for Integrative Medicine, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (H.-L.W.); (L.W.)
| | - Chang-Ying Zhao
- Department of Endocrinology, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China;
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Guangdong Academy of Sciences, Guangdong Provincial People’s Hospital Joint Research Laboratory on Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong 999077, China
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18
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The Role of SMAD4 Inactivation in Epithelial-Mesenchymal Plasticity of Pancreatic Ductal Adenocarcinoma: The Missing Link? Cancers (Basel) 2022; 14:cancers14040973. [PMID: 35205719 PMCID: PMC8870198 DOI: 10.3390/cancers14040973] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is currently one of the deadliest cancers. Despite the progress that has been made in the research of patient care and the understanding of pancreatic cancer, the survival rate remains mediocre. SMAD4, a tumor-suppressor gene, is specifically inactivated in 50–55% of pancreatic cancers. The role of SMAD4 protein loss in PDAC remains controversial, but seems to be associated with worse overall survival and metastasis. Here, we review the function of SMAD4 inactivation in the context of a specific biological process called epithelial–mesenchymal transition, as it has been increasingly associated with tumor formation, metastasis and resistance to therapy. By improving our understanding of these molecular mechanisms, we hope to find new targets for therapy and improve the care of patients with PDAC. Abstract Pancreatic ductal adenocarcinoma (PDAC) presents a five-year survival rate of 10% and its incidence increases over the years. It is, therefore, essential to improve our understanding of the molecular mechanisms that promote metastasis and chemoresistance in PDAC, which are the main causes of death in these patients. SMAD4 is inactivated in 50% of PDACs and its loss has been associated with worse overall survival and metastasis, although some controversy still exists. SMAD4 is the central signal transducer of the transforming growth factor-beta (TGF-beta) pathway, which is notably known to play a role in epithelial–mesenchymal transition (EMT). EMT is a biological process where epithelial cells lose their characteristics to acquire a spindle-cell phenotype and increased motility. EMT has been increasingly studied due to its potential implication in metastasis and therapy resistance. Recently, it has been suggested that cells undergo EMT transition through intermediary states, which is referred to as epithelial–mesenchymal plasticity (EMP). The intermediary states are characterized by enhanced aggressiveness and more efficient metastasis. Therefore, this review aims to summarize and analyze the current knowledge on SMAD4 loss in patients with PDAC and to investigate its potential role in EMP in order to better understand its function in PDAC carcinogenesis.
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19
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Botrus G, Uson Junior PLS, Raman P, Kaufman AE, Kosiorek H, Yin J, Fu Y, Majeed U, Sonbol MB, Ahn DH, Chang IW, Drusbosky LM, Dada H, Starr J, Borad M, Mody K, Bekaii-Saab TS. Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival. Front Oncol 2022; 11:794009. [PMID: 35083150 PMCID: PMC8784799 DOI: 10.3389/fonc.2021.794009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Background Plasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation. Methods Patients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS). Results A total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037). Conclusions Initial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.
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Affiliation(s)
- Gehan Botrus
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Pedro Luiz Serrano Uson Junior
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States.,Center for Personalized Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Puneet Raman
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Adrienne E Kaufman
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Heidi Kosiorek
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Jun Yin
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Yu Fu
- Guardant Health, Inc., Redwood City, CA, United States
| | - Umair Majeed
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Mohamad Bassam Sonbol
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Daniel H Ahn
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Isabela W Chang
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | | | - Hiba Dada
- Guardant Health, Inc., Redwood City, CA, United States
| | - Jason Starr
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Mitesh Borad
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States.,Center of individualized Medicine, Mayo Clinic, Rochester, MN, United States.,Mayo Clinic Cancer Center, Phoenix, AZ, United States
| | - Kabir Mody
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Tanios S Bekaii-Saab
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
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20
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Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
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Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
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21
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Casà C, Piras A, D’Aviero A, Preziosi F, Mariani S, Cusumano D, Romano A, Boskoski I, Lenkowicz J, Dinapoli N, Cellini F, Gambacorta MA, Valentini V, Mattiucci GC, Boldrini L. The impact of radiomics in diagnosis and staging of pancreatic cancer. Ther Adv Gastrointest Endosc 2022; 15:26317745221081596. [PMID: 35342883 PMCID: PMC8943316 DOI: 10.1177/26317745221081596] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 02/02/2022] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Pancreatic cancer (PC) is one of the most aggressive tumours, and better risk stratification among patients is required to provide tailored treatment. The meaning of radiomics and texture analysis as predictive techniques are not already systematically assessed. The aim of this study is to assess the role of radiomics in PC. METHODS A PubMed/MEDLINE and Embase systematic review was conducted to assess the role of radiomics in PC. The search strategy was 'radiomics [All Fields] AND ("pancreas" [MeSH Terms] OR "pancreas" [All Fields] OR "pancreatic" [All Fields])' and only original articles referred to PC in humans in the English language were considered. RESULTS A total of 123 studies and 183 studies were obtained using the mentioned search strategy on PubMed and Embase, respectively. After the complete selection process, a total of 56 papers were considered eligible for the analysis of the results. Radiomics methods were applied in PC for assessment technical feasibility and reproducibility aspects analysis, risk stratification, biologic or genomic status prediction and treatment response prediction. DISCUSSION Radiomics seems to be a promising approach to evaluate PC from diagnosis to treatment response prediction. Further and larger studies are required to confirm the role and allowed to include radiomics parameter in a comprehensive decision support system.
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Affiliation(s)
- Calogero Casà
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | | | - Andrea D’Aviero
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesco Preziosi
- Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Silvia Mariani
- Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Davide Cusumano
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Angela Romano
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ivo Boskoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy
| | - Jacopo Lenkowicz
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Nicola Dinapoli
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesco Cellini
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Antonietta Gambacorta
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Vincenzo Valentini
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gian Carlo Mattiucci
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Boldrini
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
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22
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Zhang J, Zhang M, Liang Y, Liu M, Huang Z. Downregulation of Smad4 expression confers chemoresistance against imatinib mesylate to chronic myeloid leukemia K562 cells. Hematology 2021; 27:43-52. [PMID: 34957936 DOI: 10.1080/16078454.2021.2010331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Objective: Imatinib mesylate (IM), a tyrosine kinase inhibitor, exhibits clinically prominent effects against chronic myeloid leukemia (CML); however, a few patients have shown resistance to IM treatment, resulting in disease progression. Smad4 is a tumor inhibitor that transduces TGF-β signaling and modulates genomic stability. Previous studies have indicated that decreased Smad4 expression played a bidirectional role in chemosensitivity in many types of cancers. Therefore, this study aims to evaluate the association between IM sensitivity and decreased Smad4 expression in human CML K562 cells.Methods: Bone marrow (BM) samples were acquired from the patients prior to treatment. qRT-PCR, Western Blotting (WB), colony formation assay (CFA), and apoptosis assay were used to detect relevant indices.Results: Smad4 expression was downregulated in the bone marrow and plasma of patients with multidrug-resistant CML as well as IM-resistant K562 (K562R) cells compared with samples collected from CML patients and K562 cells. Smad4 overexpression inhibited IM-treated K562R cell proliferation and augmented apoptosis, whereas Smad4 silencing promoted viability and inhibited apoptosis in IM-treated K562 cells. In addition, Smad4 expression was inversely correlated with laminin subunit gamma 1 (LAMC1) expression. The upregulation or downregulation of LAMC1 expression partially abolished the effect of Smad4 overexpression or silencing on the IM resistance of CML cells.Conclusion: The downregulation of Smad4 expression might induce drug resistance in CML cells and displayed a possible mechanism through which Smad4 modulates CML cell survival and apoptosis upon IM treatment.
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Affiliation(s)
- Jiangzhao Zhang
- Department of Hematology, Jingzhou Central Hospital, Institute of Hematology, Yangtze University, Jingzhou, People's Republic of China
| | - Min Zhang
- Department of Nephrology, Jingzhou Central Hospital, Jingzhou, People's Republic of China
| | - Yan Liang
- Department of Hematology, Jingzhou Central Hospital, Jingzhou, People's Republic of China
| | - Min Liu
- Department of Hematology, Jingzhou Central Hospital, Jingzhou, People's Republic of China
| | - Zhiping Huang
- Department of Hematology, Jingzhou Central Hospital, Institute of Hematology, Yangtze University, Jingzhou, People's Republic of China
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23
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Malakoti F, Targhazeh N, Karimzadeh H, Mohammadi E, Asadi M, Asemi Z, Alemi F. The Multiple Function of lncRNA MALAT1 in Cancer Occurrence and Progression. Chem Biol Drug Des 2021; 101:1113-1137. [PMID: 34918470 DOI: 10.1111/cbdd.14006] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/29/2021] [Accepted: 12/09/2021] [Indexed: 11/28/2022]
Abstract
Long non-coding RNAs (lncRNAs) have received particular attention in the last decade due to its engaging in carcinogenesis and tumorigenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that plays physiological and pathological roles in many aspects of genome function as well as biological processes involved in cell development, differentiation, proliferation, invasion, and migration. In this article, we will review the effects of lncRNA MALAT1 on the progression of six prevalent human cancers by focusing on MALAT1 ability to regulate post-transcriptional modification and signaling pathways.
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Affiliation(s)
- Faezeh Malakoti
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haniye Karimzadeh
- Department of Clinical Biochemistry, School of Pharmacy & Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Erfan Mohammadi
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.,Drugs Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Drugs Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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24
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TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters. J Biol Chem 2021; 297:101162. [PMID: 34481843 PMCID: PMC8498470 DOI: 10.1016/j.jbc.2021.101162] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/23/2021] [Accepted: 08/31/2021] [Indexed: 01/10/2023] Open
Abstract
Cyclin-dependent kinase 7 (CDK7) is a master regulatory kinase that drives cell cycle progression and stimulates expression of oncogenes in a myriad of cancers. Inhibitors of CDK7 (CDK7i) are currently in clinical trials; however, as with many cancer therapies, patients will most likely experience recurrent disease due to acquired resistance. Identifying targets underlying CDK7i resistance will facilitate prospective development of new therapies that can circumvent such resistance. Here we utilized triple-negative breast cancer as a model to discern mechanisms of resistance as it has been previously shown to be highly responsive to CDK7 inhibitors. After generating cell lines with acquired resistance, high-throughput RNA sequencing revealed significant upregulation of genes associated with efflux pumps and transforming growth factor-beta (TGF-β) signaling pathways. Genetic silencing or pharmacological inhibition of ABCG2, an efflux pump associated with multidrug resistance, resensitized resistant cells to CDK7i, indicating a reliance on these transporters. Expression of activin A (INHBA), a member of the TGF-β family of ligands, was also induced, whereas its intrinsic inhibitor, follistatin (FST), was repressed. In resistant cells, increased phosphorylation of SMAD3, a downstream mediator, confirmed an increase in activin signaling, and phosphorylated SMAD3 directly bound the ABCG2 promoter regulatory region. Finally, pharmacological inhibition of TGF-β/activin receptors or genetic silencing of SMAD4, a transcriptional partner of SMAD3, reversed the upregulation of ABCG2 in resistant cells and phenocopied ABCG2 inhibition. This study reveals that inhibiting the TGF-β/Activin-ABCG2 pathway is a potential avenue for preventing or overcoming resistance to CDK7 inhibitors.
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25
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Pao SI, Lin LT, Chen YH, Chen CL, Chen JT. Repression of Smad4 by MicroRNA-1285 moderates TGF-β-induced epithelial-mesenchymal transition in proliferative vitreoretinopathy. PLoS One 2021; 16:e0254873. [PMID: 34383767 PMCID: PMC8360606 DOI: 10.1371/journal.pone.0254873] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
The purpose of this study was to assess whether microRNA (miR)-1285 can suppress the epithelial-mesenchymal transition (EMT) in retinal pigment epithelial cells. Expression of miR-1285 was evaluated using quantitative real-time polymerase chain reaction (RT-qPCR). The features of EMT were assessed using Western blotting, immunocytochemical staining, scratch wound healing tests, modified Boyden chamber assay, and collagen gel contraction assay. A rabbit model of proliferative vitreoretinopathy (PVR) was used for in vivo testing, which involved the induction of PVR by injection of transfected ARPE cells into the vitreous chamber. Luciferase reporter assay was performed to identify the putative target of miR-1285. The expression of miR-1285 was downregulated in ARPE-19 cells treated with transforming growth factor (TGF)-β. Overexpression of miR-1285 led to upregulation of zonula occludens-1, downregulation of α-smooth muscle actin and vimentin, cell migration and cell contractility-all EMT features-in the TGF-β2-treated ARPE-19 cells. The reporter assay indicated that the 3' untranslated region of Smad4 was the direct target of miR1285. PVR progression was alleviated in the miR-1285 transfected rabbits. In conclusion, overexpression of miR-1285 attenuates TGF-β2-induced EMT in a rabbit model of PVR, and the effect of miR-1285 in PVR is dependent on Smad4. Further research is warranted to develop a feasible therapeutic approach for the prevention and treatment of PVR.
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Affiliation(s)
- Shu-I Pao
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Le-Tien Lin
- Department of Ophthalmology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yi-Hao Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Ching-Long Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Jiann-Torng Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
- * E-mail:
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26
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Hayashi H, Higashi T, Miyata T, Yamashita Y, Baba H. Recent advances in precision medicine for pancreatic ductal adenocarcinoma. Ann Gastroenterol Surg 2021; 5:457-466. [PMID: 34337294 PMCID: PMC8316748 DOI: 10.1002/ags3.12436] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide. Although advances in systemic chemotherapy for PDAC have improved survival outcomes for patients with the disease, chemoresistance is a major treatment issue for unselected PDAC patient populations. The existence of heterogeneity caused by a mixture of tumor cells and stromal cells produces chemoresistance and limits the targeted therapy of PDAC. Advances in precision medicine for PDACs according to the genetics and molecular biology of this disease may represent the next alternative approach to overcome the heterogeneity of different patients and improve survival outcomes for this poor prognostic disease. The genetic alteration of PDAC is characterized by four genes that are frequently mutated (KRAS, TP53, CDKN2A, and SMAD4). Furthermore, several genetic and molecular profiling studies have revealed that up to 25% of PDACs harbor actionable alterations. In particular, DNA repair dysfunction, including cases with BRCA mutations, is a causal element of sensitivity to platinum-based anti-cancer agents and poly-ADP ribose polymerase (PARP) inhibitors. A deep understanding of the molecular and cellular crosstalk in the tumor microenvironment helps to establish scientifically rational treatment strategies for cancers that show specific molecular profiles. Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Takaaki Higashi
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Tatsunori Miyata
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Yo‐ichi Yamashita
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Hideo Baba
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
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27
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SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy. Oncogene 2021; 40:2539-2552. [PMID: 33686239 DOI: 10.1038/s41388-021-01726-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor β (TGFβ) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGFβ-treatment and the loss of SMAD4, a downstream member of TGFβ signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGFβ-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGFβ signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGFβ signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker.
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28
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Guo X, Li M, Wang X, Pan Y, Li J. Correlation between loss of Smad4 and clinical parameters of non-small cell lung cancer: an observational cohort study. BMC Pulm Med 2021; 21:111. [PMID: 33794845 PMCID: PMC8017835 DOI: 10.1186/s12890-021-01480-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 03/24/2021] [Indexed: 02/08/2023] Open
Abstract
Background SMAD4 has been found to be inactivated to varying degrees in many types of cancer; the purpose of this study was to investigate the correlation between SMAD4 expression in non-small cell lung cancer (NSCLC) and clinical pathological parameters. Methods The serum concentration of SMAD4 was measured by enzyme-linked immunosorbent assay and its histological expression was quantified by immunohistochemistry. Results The serum concentration of Smad4 in patients with NSCLC was lower than that in benign lung disease patients and healthy individuals (P < 0.001) and its concentration was related to the histological classification, pathological differentiation, lymphatic metastasis and clinical stage of NSCLC. The sensitivity and specificity of serum Smad4 were 91.56% and 61.56% for screening NSCLC from healthy individuals and 84.55% and 60.36% for screening NSCLC from patients with benign lung disease. Logistic regression analysis showed that the degree of cell differentiation (P < 0.001), lymph node metastasis (P < 0.001) and clinical stage of NSCLC (P = 0.007) affected the expression of Smad4, and had a strong correlation with the expression of Smad4. The expression of Smad4 in NSCLC tissues was lower than that in normal lung tissues (P = 0.009) and its expression was related to the degree of tissue differentiation, lymph node metastasis and clinical stage (P < 0.05). Conclusions The downregulation or deletion of Smad4 is related to the malignant biological behavior of NSCLC and serum Smad4 could be considered as a potential molecular indicator for diagnosis and evaluation of NSCLC.
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Affiliation(s)
- Xiangjun Guo
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Lianyungang City, Lianyungang, Jiangsu, China
| | - Mengmeng Li
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Lianyungang City, Lianyungang, Jiangsu, China
| | - Xin Wang
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Lianyungang City, Lianyungang, Jiangsu, China
| | - Yun Pan
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Lianyungang City, Lianyungang, Jiangsu, China
| | - Jiashu Li
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Lianyungang City, Lianyungang, Jiangsu, China.
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Prieto-García E, Díaz-García CV, Agudo-López A, Pardo-Marqués V, García-Consuegra I, Asensio-Peña S, Alonso-Riaño M, Pérez C, Gómez C, Adeva J, Paz-Ares L, López-Martín JA, Agulló-Ortuño MT. Tumor-Stromal Interactions in a Co-Culture Model of Human Pancreatic Adenocarcinoma Cells and Fibroblasts and Their Connection with Tumor Spread. Biomedicines 2021; 9:biomedicines9040364. [PMID: 33807441 PMCID: PMC8065458 DOI: 10.3390/biomedicines9040364] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/20/2021] [Accepted: 03/27/2021] [Indexed: 12/22/2022] Open
Abstract
One key feature of pancreatic ductal adenocarcinoma (PDAC) is a dense desmoplastic reaction that has been recognized as playing important roles in metastasis and therapeutic resistance. We aim to study tumor-stromal interactions in an in vitro coculture model between human PDAC cells (Capan-1 or PL-45) and fibroblasts (LC5). Confocal immunofluorescence, Enzyme-Linked Immunosorbent Assay (ELISA), and Western blotting were used to evaluate the expressions of activation markers; cytokines arrays were performed to identify secretome profiles associated with migratory and invasive properties of tumor cells; extracellular vesicle production was examined by ELISA and transmission electron microscopy. Coculture conditions increased FGF-7 secretion and α-SMA expression, characterized by fibroblast activation and decreased epithelial marker E-cadherin in tumor cells. Interestingly, tumor cells and fibroblasts migrate together, with tumor cells in forming a center surrounded by fibroblasts, maximizing the contact between cells. We show a different mechanism for tumor spread through a cooperative migration between tumor cells and activated fibroblasts. Furthermore, IL-6 levels change significantly in coculture conditions, and this could affect the invasive and migratory capacities of cells. Targeting the interaction between tumor cells and the tumor microenvironment might represent a novel therapeutic approach to advanced PDAC.
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Affiliation(s)
- Elena Prieto-García
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
| | - C. Vanesa Díaz-García
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
| | - Alba Agudo-López
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
| | - Virginia Pardo-Marqués
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
| | - Inés García-Consuegra
- Proteomic Unit, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (I.G.-C.); (S.A.-P.)
- Biomedical Research Networking Center (CIBERER), U723, Instituto de Salud Carlos III. Av. de Córdoba S/N, 28041 Madrid, Spain
| | - Sara Asensio-Peña
- Proteomic Unit, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (I.G.-C.); (S.A.-P.)
- Laboratory of Rare Diseases, Mitochondrial &Neuromuscular Diseases, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain
| | - Marina Alonso-Riaño
- Pathology Department, Hospital Universitario 12 de Octubre, Av. de Córdoba S/N, 28041 Madrid, Spain;
| | - Carlos Pérez
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
| | - Carlos Gómez
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Av. de Córdoba S/N, 28041 Madrid, Spain; (C.G.); (J.A.)
| | - Jorge Adeva
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Av. de Córdoba S/N, 28041 Madrid, Spain; (C.G.); (J.A.)
| | - Luis Paz-Ares
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Av. de Córdoba S/N, 28041 Madrid, Spain; (C.G.); (J.A.)
- Biomedical Research Networking Center (CIBERONC), Instituto de Salud Carlos III, Av. de Córdoba S/N, 28041 Madrid, Spain
- Medicine Department, Facultad de Medicina y Cirugía (UCM), Av. de Séneca, 2, 28040 Madrid, Spain
| | - José A. López-Martín
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Av. de Córdoba S/N, 28041 Madrid, Spain; (C.G.); (J.A.)
| | - M. Teresa Agulló-Ortuño
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Hospital 12 de Octubre (i+12), Av. de Córdoba S/N, 28041 Madrid, Spain; (E.P.-G.); (C.V.D.-G.); (A.A.-L.); (V.P.-M.); (C.P.); (L.P.-A.); (J.A.L.-M.)
- Biomedical Research Networking Center (CIBERONC), Instituto de Salud Carlos III, Av. de Córdoba S/N, 28041 Madrid, Spain
- Department of Nursing, Physiotherapy and Occupational Therapy, Facultad de Fisioterapia y Enfermería, (UCLM), Av. de Carlos III, S/N, 45071 Toledo, Spain
- Correspondence:
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Kumar R, Kumar R, Tanwar P. Structural based screening of potential inhibitors of SMAD4: a step towards personalized medicine for gall bladder and other associated cancers. Mol Divers 2021; 25:1945-1961. [PMID: 33751339 DOI: 10.1007/s11030-021-10210-w] [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: 10/21/2020] [Accepted: 03/14/2021] [Indexed: 12/24/2022]
Abstract
Gall bladder cancer (GBC) is an aggressive and most common malignancy of biliary tract lacking effective treatment due to unavailability of suitable biomarkers and therapeutics. SMAD4 is an essential mediator of transforming growth factor-β pathway involved in various cellular processes like growth, differentiation and apoptosis and also recognized as therapeutic target for GBC and other gastrointestinal tract cancers. In the present study, 3D structure of SMAD4 mutants was optimized through molecular dynamics simulation (MDS) along with wildtype. Furthermore, binding site of protein was predicted through hybrid approach and structural based virtual screening against two drug libraries was performed followed by docking. MDS of top docking score protein-ligand complexes were carried, and binding free energy was rescored. Two potential inhibitors, namely ZINC2098840 and ZINC8789167, were screened that displayed higher binding affinity towards mutant proteins compared with wildtype and both hydrophilic as well as hydrophobic interactions play a crucial role during protein-ligand binding. Current study identified novel and potent inhibitors of SMAD4 mutant that could be used as a drug candidate for the development of personalized medicine for gall bladder and other associated cancers.
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Affiliation(s)
- Rakesh Kumar
- Dr.B.R.A.-Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rahul Kumar
- Dr.B.R.A.-Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Pranay Tanwar
- Dr.B.R.A.-Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Crosstalk between miRNAs and signaling pathways involved in pancreatic cancer and pancreatic ductal adenocarcinoma. Eur J Pharmacol 2021; 901:174006. [PMID: 33711308 DOI: 10.1016/j.ejphar.2021.174006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/19/2021] [Accepted: 03/02/2021] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide with 5-year survival rates below 8%. Most patients with PC and pancreatic ductal adenocarcinoma (PDAC) die after relapse and cancer progression as well as resistance to treatment. Pancreatic tumors contain a high desmoplastic stroma that forms a rigid mass and has a potential role in tumor growth and metastasis. PC initiates from intraepithelial neoplasia lesions leading to invasive cancer through various pathways. These lesions harbor particular changes in signaling pathways involved in the tumorigenesis process. These events affect both the epithelial cells, including the tumor and the surrounding stroma, and eventually lead to the formation of complex signaling networks. Genetic studies of PC have revealed common molecular features such as the presence of mutations in KRAS gene in more than 90% of patients, as well as the inactivation or deletion mutations of some tumor suppressor genes including TP53, CDKN2A, and SMAD4. In recent years, studies have also identified different roles of microRNAs in PC pathogenesis as well as their importance in PC diagnosis and treatment, and their involvement in various signaling pathways. In this study, we discussed the most common pathways involved in PC and PDAC as well as their role in tumorigenesis and progression. Furthermore, the miRNAs participating in the regulation of these signaling pathways in PC progression are summarized in this study. Therefore, understanding more about pathways involved in PC can help with the development of new and effective therapies in the future.
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Gu JF, Fu W, Qian HX, Gu WX, Zong Y, Chen Q, Lu L. TBL1XR1 induces cell proliferation and inhibit cell apoptosis by the PI3K/AKT pathway in pancreatic ductal adenocarcinoma. World J Gastroenterol 2020; 26:3586-3602. [PMID: 32742128 PMCID: PMC7366057 DOI: 10.3748/wjg.v26.i25.3586] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/09/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. Identification of diagnostic and therapeutic biomarkers for PDAC is urgently needed. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) has been linked to the progression of various human cancers. Nevertheless, the function and role of TBL1XR1 in pancreatic cancers are unclear.
AIM To elucidate the function and potential mechanism of TBL1XR1 in the development of PDAC.
METHODS Ninety patients with histologically-confirmed PDAC were included in this study. PDAC tumor samples and cell lines were used to determine the expression of TBL1XR1. CCK-8 assays and colony formation assays were carried out to assess PDAC cell viability. Flow cytometry was performed to measure the changes in the cell cycle and cell apoptosis. Changes in related protein expression were measured by western blot analysis. Animal analysis was conducted to confirm the impact of TBL1XR1 in vivo.
RESULTS Patients with TBL1XR1-positive tumors had worse overall survival than those with TBL1XR1-negative tumors. Moreover, we found that TBL1XR1 strongly promoted PDAC cell proliferation and inhibited PDAC cell apoptosis. Moreover, knockdown of TBL1XR1 induced G0/G1 phase arrest. In vivo animal studies confirmed that TBL1XR1 accelerated tumor cell growth. The results of western blot analysis showed that TBL1XR1 might play a key role in regulating PDAC cell proliferation and apoptosis via the PI3K/AKT pathway.
CONCLUSION TBL1XR1 promoted PDAC cell progression and might be an effective diagnostic and therapeutic marker for pancreatic cancer.
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Affiliation(s)
- Jian-Feng Gu
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Wei Fu
- Department of Oncology, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Hai-Xin Qian
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Wen-Xiu Gu
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Yang Zong
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Qian Chen
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Long Lu
- Department of Oncology, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
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Dardare J, Witz A, Merlin JL, Gilson P, Harlé A. SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2020; 21:E3534. [PMID: 32429474 PMCID: PMC7278913 DOI: 10.3390/ijms21103534] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/12/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.
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Affiliation(s)
| | | | | | | | - Alexandre Harlé
- Université de Lorraine, CNRS UMR7039 CRAN, Service de Biopathologie, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-lès-Nancy, France; (J.D.); (A.W.); (J.-L.M.); (P.G.)
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Nelson SR, Walsh N. Genetic Alterations Featuring Biological Models to Tailor Clinical Management of Pancreatic Cancer Patients. Cancers (Basel) 2020; 12:E1233. [PMID: 32423157 PMCID: PMC7281628 DOI: 10.3390/cancers12051233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide. This high mortality rate is due to the disease's lack of symptoms, resulting in a late diagnosis. Biomarkers and treatment options for pancreatic cancer are also limited. In order to overcome this, new research models and novel approaches to discovering PDAC biomarkers are required. In this review, we outline the hereditary and somatic causes of PDAC and provide an overview of the recent genome wide association studies (GWAS) and pathway analysis studies. We also provide a summary of some of the systems used to study PDAC, including established and primary cell lines, patient-derived xenografts (PDX), and newer models such as organoids and organ-on-chip. These ex vitro laboratory systems allow for critical research into the development and progression of PDAC.
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Affiliation(s)
| | - Naomi Walsh
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland;
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Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT. Eur J Cell Biol 2020; 99:151076. [PMID: 32439219 DOI: 10.1016/j.ejcb.2020.151076] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 03/20/2020] [Accepted: 03/20/2020] [Indexed: 12/22/2022] Open
Abstract
Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4-/- cells were devoid of significant Smad4 induction compared to Par-4+/+ cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G1 arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4-/-), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.
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Bozza M, Green EW, Espinet E, De Roia A, Klein C, Vogel V, Offringa R, Williams JA, Sprick M, Harbottle RP. Novel Non-integrating DNA Nano-S/MAR Vectors Restore Gene Function in Isogenic Patient-Derived Pancreatic Tumor Models. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 17:957-968. [PMID: 32420409 PMCID: PMC7218229 DOI: 10.1016/j.omtm.2020.04.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 04/22/2020] [Indexed: 12/22/2022]
Abstract
We describe herein non-integrating minimally sized nano-S/MAR DNA vectors, which can be used to genetically modify dividing cells in place of integrating vectors. They represent a unique genetic tool, which avoids vector-mediated damage. Previous work has shown that DNA vectors comprising a mammalian S/MAR element can provide persistent mitotic stability over hundreds of cell divisions, resisting epigenetic silencing and thereby allowing sustained transgene expression. The composition of the original S/MAR vectors does present some inherent limitations that can provoke cellular toxicity. Herein, we present a new system, the nano-S/MAR, which drives higher transgene expression and has improved efficiency of establishment, due to the minimal impact on cellular processes and perturbation of the endogenous transcriptome. We show that these features enable the hitherto challenging genetic modification of patient-derived cells to stably restore the tumor suppressor gene SMAD4 to a patient-derived SMAD4 knockout pancreatic cancer line. Nano-S/MAR modification does not alter the molecular or phenotypic integrity of the patient-derived cells in cell culture and xenograft mouse models. In conclusion, we show that these DNA vectors can be used to persistently modify a range of cells, providing sustained transgene expression while avoiding the risks of insertional mutagenesis and other vector-mediated toxicity.
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Affiliation(s)
- Matthias Bozza
- DNA Vector Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
| | - Edward W Green
- Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Elisa Espinet
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Alice De Roia
- DNA Vector Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
| | - Corinna Klein
- Stem Cells and Metastasis, Hi-Stem Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Vanessa Vogel
- Stem Cells and Metastasis, Hi-Stem Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Rienk Offringa
- Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | | | - Martin Sprick
- Stem Cells and Metastasis, Hi-Stem Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Richard P Harbottle
- DNA Vector Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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Zeng Z, Yang Y, Qing C, Hu Z, Huang Y, Zhou C, Li D, Jiang Y. Distinct expression and prognostic value of members of SMAD family in non-small cell lung cancer. Medicine (Baltimore) 2020; 99:e19451. [PMID: 32150102 PMCID: PMC7220383 DOI: 10.1097/md.0000000000019451] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the major cause of cancer mortality worldwide. Though multidisciplinary therapies have been widely used for NSCLC, its overall prognosis remains very poor, presumably owing to lack of effective prognostic biomarkers. SMAD, a well-known transcription factor, plays an essential role in carcinogenesis. Aberrant expression of SMAD have been found in various cancers, and may be regarded as prognostic indicator for some malignancies. However, the expression and prognostic role of SMAD family member, especially at the mRNA level, remain elusive in NSCLC. In the present study, we report the distinct expression and prognostic value of individual SMAD in patients with NSCLC by analyzing several online databases including ONCOMINE, Gene Expression Profiling Interactive Analysis, Human Protein Atlas database, Kaplan-Meier plotter, cBioPortal, and Database for Annotation, Visualization and Integrated Discovery. The mRNA levels of SMAD6/7/9 in NSCLC were significantly down-regulated in NSCLC, and aberrant SMAD2/3/4/5/6/7/9 mRNA levels were all correlated with the prognosis of NSCLC. Collectively, SMAD2/3/4/5/6/7/9 may server as prognostic biomarkers and potential targets for NSCLC, and thus facilitate the customized treatment strategies for NSCLC patients.
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Affiliation(s)
- Zhenguo Zeng
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University
| | - Yuting Yang
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University
| | - Cheng Qing
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University
| | - Zhiguo Hu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University
- Department of Critical Care Medicine, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia
| | - Yiming Huang
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University
| | - Chaoqi Zhou
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University
| | - Dan Li
- Department of Respiratory and Critical Care Medicine
| | - Yanxia Jiang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
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Amrutkar M, Larsen EK, Aasrum M, Finstadsveen AV, Andresen PA, Verbeke CS, Gladhaug IP. Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor. Cells 2020; 9:cells9010227. [PMID: 31963309 PMCID: PMC7016771 DOI: 10.3390/cells9010227] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/10/2020] [Accepted: 01/14/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored KRAS and TP53 mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology.
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Affiliation(s)
- Manoj Amrutkar
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway; (E.K.L.); (M.A.)
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Blindern, 0318 Oslo, Norway;
- Correspondence: ; Tel.: +47-409-94-132
| | - Emma Kristine Larsen
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway; (E.K.L.); (M.A.)
| | - Monica Aasrum
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway; (E.K.L.); (M.A.)
| | - Anette Vefferstad Finstadsveen
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway; (A.V.F.); (P.A.A.); (C.S.V.)
| | - Per Arne Andresen
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway; (A.V.F.); (P.A.A.); (C.S.V.)
| | - Caroline S. Verbeke
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway; (A.V.F.); (P.A.A.); (C.S.V.)
- Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway
| | - Ivar P. Gladhaug
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, Blindern, 0318 Oslo, Norway;
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Nydalen, 0424 Oslo, Norway
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Ginkgolic Acid, a SUMO-1 Inhibitor, Inhibits the Progression of Oral Squamous Cell Carcinoma by Alleviating SUMOylation of SMAD4. MOLECULAR THERAPY-ONCOLYTICS 2019; 16:86-99. [PMID: 31970286 PMCID: PMC6965518 DOI: 10.1016/j.omto.2019.12.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 12/07/2019] [Indexed: 12/30/2022]
Abstract
Small ubiquitin-related modifiers (SUMO) represent a class of ubiquitin-like proteins that are conjugated, like ubiquitin, by a set of enzymes to form cellular regulatory proteins, and play key roles in the control of cell proliferation, differentiation, and apoptosis. We found that ginkgolic acid (GA) can significantly reduce cell vitality in a dose- and time-dependent manner and can also accelerate cyto-apoptosis in both Tca8113 and Cal-27 cells. Migration and wound-healing assays were executed to determine the anti-migration effect of GA in oral squamous cell carcinoma (OSCC) cell lines. GA represses transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) markers in OSCC cell lines. This investigation is the first evidence that GA suppresses TGF-β1-induced SUMOylation of SMAD4. We show that GA affects the phosphorylation of SMAD2/3 protein and the release of SMAD4. In the xenograft mouse model, the OSCC progression was reduced by GA, effectively suppressing the growth of tumors. In addition, siSMAD4 improved cell migration and viability, which was inhibited by GA in Tca8113 cells. GA suppresses tumorigenicity and tumor progression of OSCC through inhibition of TGF-β1-induced enhancement of SUMOylation of SMAD4. Thus, GA could be a promising therapeutic for OSCC.
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Fischer CG, Wood LD. From somatic mutation to early detection: insights from molecular characterization of pancreatic cancer precursor lesions. J Pathol 2019; 246:395-404. [PMID: 30105857 DOI: 10.1002/path.5154] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/02/2018] [Accepted: 08/09/2018] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer arises from noninvasive precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), which are curable if detected early enough. Recently, these types of precursor lesions have been extensively characterized at the molecular level, defining the timing of critical genetic alterations in tumorigenesis pathways. The results of these studies deepen our understanding of tumorigenesis in the pancreas, providing novel insights into tumor initiation and progression. Perhaps more importantly, they also provide a rational foundation for early detection approaches that could allow clinical intervention prior to malignant transformation. In this review, we summarize the results of comprehensive molecular characterization of PanINs, IPMNs, and MCNs and discuss the implications for cancer biology as well as early detection. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Catherine G Fischer
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zhai S, Liu Y, Lu X, Qian H, Tang X, Cheng X, Wang Y, Shi Y, Deng X. INPP4B As A Prognostic And Diagnostic Marker Regulates Cell Growth Of Pancreatic Cancer Via Activating AKT. Onco Targets Ther 2019; 12:8287-8299. [PMID: 31632078 PMCID: PMC6790406 DOI: 10.2147/ott.s223221] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022] Open
Abstract
Background Inositol polyphosphate 4-phosphatase type II (INPP4B), a member of the PI3K/Akt signaling pathway, plays a vital role in the initiation and progression of cancers. However, its biological role in pancreatic cancer remains largely undiscovered. Our study aimed to investigate the effects of INPP4B on proliferation in pancreatic cancer and its clinical relevance. Materials and methods INPP4B expression data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Clinicopathological and survival data were retrieved from the TCGA database. CCK8 and colony formation assays were performed to measure the proliferative capacity of pancreatic cancer. Tumor xenograft models were established to measure cancer proliferative abilities in vivo. Results INPP4B was upregulated in pancreatic cancer tissue compared with normal tissue. INPP4B knockdown inhibited cell proliferation and promoted apoptosis in pancreatic cancer in vitro and in vivo. INPP4B knockdown also reduced AKT phosphorylation. Moreover, INPP4B was associated with poor overall and disease-free survival, with Cox regression analysis showing that INPP4B could serve as an independent prognostic marker. ROC curve analysis showed that INPP4B possessed moderate diagnostic value. Conclusion Collectively, INPP4B is an oncogenic gene in pancreatic cancer and could serve as a potential diagnostic marker and an independent prognostic marker, suggesting that it could be a novel therapeutic target for pancreatic cancer.
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Affiliation(s)
- Shuyu Zhai
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Yuanbin Liu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Xiongxiong Lu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Hao Qian
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Xiaomei Tang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Xi Cheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Yue Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Yusheng Shi
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Xiaxing Deng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
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Bijou I, Wang J. Evolving trends in pancreatic cancer therapeutic development. ANNALS OF PANCREATIC CANCER 2019; 2:17. [PMID: 33089149 PMCID: PMC7575122 DOI: 10.21037/apc.2019.09.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Despite advances in translational research, the overall 5-year survival for pancreatic cancer remains dismal and with rising incidence pancreatic cancer is predicted to be the second leading cause of cancer death for many developed countries. Surgical intervention followed by cytotoxic chemotherapy are currently the best options for treatment, but disease recurrence is very common. Efforts to develop new therapeutic agents and delivery systems are necessary to achieve better clinical efficacy with less toxicity. Promising prospects are arising with new preclinical and clinical therapeutic strategies using small molecule targeted therapies, RNAi, stromal therapies, and immunotherapies. With a better understanding of the biology to aid target selection and discovery of biomarkers to aid precision medicine, better opportunities will evolve to shape the therapeutic landscape, enhance patient quality of life and increase overall survival.
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Affiliation(s)
- Imani Bijou
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
| | - Jin Wang
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
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Alvarez MA, Freitas JP, Mazher Hussain S, Glazer ES. TGF-β Inhibitors in Metastatic Pancreatic Ductal Adenocarcinoma. J Gastrointest Cancer 2019; 50:207-213. [PMID: 30891677 DOI: 10.1007/s12029-018-00195-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancerrelated mortality in the USA, and the overall incidence of the disease is increasing such that it is expected to be the third leading cause of cancer-related deaths in the next decade. Minimal improvements in therapy have not changed the overall mortality rate over the past decade for patients with PDAC. The purpose of this review is to identify new data regardign the role of Transforming growth factor beta (TGF-β) based therapeuics in patients with PDAC. METHODS The literature was searched for peer reviewed manuscripts regarding the use of TGF-β inhibitors in PDAC therapy and the mechanism in which TGF-β intracellular signaling effects patient survival. RESULTS TGF-β plays a vital, context-dependent role as both a tumor suppressor and promoter of PDAC. The downstream effects of this duality play a significant role in the immunologic response of the tumor microenvironment (TME), epithelial-mesenchymal transformation (EMT), and the development of metastatic disease. Immunologic pathways have been shown to be successful targets in the treatment of other diseases, though they have not been shown efficacious in PDAC. TGF-β-mediated EMT does play a critical role in PDAC progression in the development of metastases. The use of anti-TGF-β-based therapies in phase I and II clinical trials for metastatic PDAC demonstrate the importance of understanding the role of TGF-β in PDAC progression. CONCLUSION This review clarifies the recent literature investigating the role of anti-TGF-β-based therapy in PDAC and areas ripe for targeted investigations and therapies.
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Affiliation(s)
- Marcus A Alvarez
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Júlia Pedó Freitas
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - S Mazher Hussain
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA
| | - Evan S Glazer
- Department of Surgery, University of Tennessee Health Science Center, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA.
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Huo Z, Zhai S, Weng Y, Qian H, Tang X, Shi Y, Deng X, Wang Y, Shen B. PRPF40A as a potential diagnostic and prognostic marker is upregulated in pancreatic cancer tissues and cell lines: an integrated bioinformatics data analysis. Onco Targets Ther 2019; 12:5037-5051. [PMID: 31303762 PMCID: PMC6610298 DOI: 10.2147/ott.s206039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 05/31/2019] [Indexed: 12/15/2022] Open
Abstract
Background Pre-mRNA processing factor 40 homolog A (PRPF40A) is an important protein involved in pre-mRNA splicing and is expressed in a variety of cell types. However, the function of PRPF40A in pancreatic cancer remains unclear. Therefore, our study is to investigate the role of PRPF40A in the pathogenesis of pancreatic cancer. Materials and methods We extracted expression data and clinical information of PRPF40A from different online databases, including the Cancer Genome Atlas (TCGA), Oncomine and the Gene Expression Omnibus (GEO). Subsequently, samples were collected from patients to validate gene expression using qPCR, Western blotting and immunohistochemical (IHC) analyses. Receiver operating characteristic (ROC) and Kaplan-Meier curve were used to evaluate the diagnostic and prognostic potential. Colony formation assays and CCK-8 assays were performed to measure the proliferative capacity of pancreatic cancer. Finally, gene ontology (GO) and pathway enrichment analyses of co-expressed genes of PRPF40A were conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Results We found that PRPF40A was upregulated based on data from both the online databases and our samples. PRPF40A possessed a significant diagnostic value, and its overexpression was associated with poor prognosis. PRPF40A knockdown inhibited cell proliferation in pancreatic cancer. GO and pathway analysis showed that the co-expressed genes were mainly involved in viral processing, mRNA splicing and the AMPK signaling pathway. Conclusion The results suggest that PRPF40A is an oncogene and can serve as a diagnostic and prognostic biomarker for pancreatic cancer. However, the underlying mechanisms remain to be elucidated.
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Affiliation(s)
- Zhen Huo
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Shuyu Zhai
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Yuanchi Weng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Hao Qian
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Xiaomei Tang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Yusheng Shi
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Xiaxing Deng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Yue Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
| | - Baiyong Shen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China
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Jiang X, Zhang Z, Song C, Deng H, Yang R, Zhou L, Sun Y, Zhang Q. Glaucocalyxin A reverses EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Chem Biol Interact 2019; 307:158-166. [PMID: 31059706 DOI: 10.1016/j.cbi.2019.05.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 04/27/2019] [Accepted: 05/03/2019] [Indexed: 02/07/2023]
Abstract
Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-β1 (TGF-β1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-β-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.
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Affiliation(s)
- Xiubo Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Zhenhao Zhang
- The First Clinical Medical College, Nanjing Medical University, 101Longmian Avenue, Jiangning District, Nanjing 211166, People's Republic of China
| | - Changqin Song
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Hanzhi Deng
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Runyu Yang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Lvqi Zhou
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Yang Sun
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
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MiR-144 inhibits growth and metastasis in colon cancer by down-regulating SMAD4. Biosci Rep 2019; 39:BSR20181895. [PMID: 30745456 PMCID: PMC6395301 DOI: 10.1042/bsr20181895] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 01/10/2019] [Accepted: 01/30/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (MiRs) are thought to display regulator action in tumor suppression and oncogenesis. miR-144 plays an important role in the development of various cancers, such as colorectal cancer, breast cancer, and lung cancer, by targetting different molecules potentially involved in many signaling pathways. SMAD4 is a common signaling during tumor progression, and it can inhibit cell proliferation and promote cell motility in most epithelial cells. The present study focused on the effect of miR-144 and SMAD4 on colon cancer in order to find the novel gene therapy target for the treatment of colon cancer. Quantitative real-time polymerase chain reaction was used to assess the expression level of miR-144 in colon cancer tissues and SW620 cells. MTT assay, scratch test, and transwell assay were used to evaluate cell proliferation, migration, and invasion, respectively. Moreover, luciferase assays were utilized to identify the predictive effect of miR-144 on SMAD4. Western blotting was performed to determine the relative expression of protein related to SMAD4. We found miR-144 level was significantly lower in colon cancer tissues and SW620 cells. Moreover, SMAD4 level, both in mRNA and protein, was obviously elevated in colon cancer tissues. Further, miR-144 mimics treatment inhibited cells proliferation, invasion, and migration. Fluorescence intensity of miR-144 mimics group in wild type cells was decreased. MiR-144 mimics repressed the SMAD4 expression both in mRNA and protein. These findings about miR-144/SMAD4 pair provide a novel therapeutic method for colon cancer patients.
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Awaji M, Singh RK. Cancer-Associated Fibroblasts' Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2019; 11:cancers11030290. [PMID: 30832219 PMCID: PMC6468677 DOI: 10.3390/cancers11030290] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 02/22/2019] [Accepted: 02/26/2019] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier to hinder chemotherapy and actively contributes to tumor progression and metastasis. CAFs represent a multifunctional subset of PDAC microenvironment and contribute to tumor initiation and progression through ECM deposition and remodeling, as well as the secretion of paracrine factors. Attempts to resolve desmoplasia by targeting CAFs can render an adverse outcome, which is likely due to CAFs heterogeneity. Recent reports describe subsets of CAFs that assume more secretory functions, in addition to the typical myofibroblast phenotype. Here, we review the literature and describe the relationship between CAFs and inflammation and the role of the secretory-CAFs in PDAC.
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Affiliation(s)
- Mohammad Awaji
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985845 UNMC, Omaha, NE 68198-5845, USA.
- Department of Pathology and Laboratory Medicine, King Fahad Specialist Hospital-Dammam, Dammam 31444, Saudi Arabia.
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985845 UNMC, Omaha, NE 68198-5845, USA.
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Yakovenko A, Cameron M, Trevino JG. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J Gastrointest Surg 2018; 10:95-106. [PMID: 30622678 PMCID: PMC6314860 DOI: 10.4240/wjgs.v10.i9.95] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/01/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies.
Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta (TGF-β), myostatin and activin, IGF-1/PI3K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.
Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.
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Affiliation(s)
- Anastasiya Yakovenko
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Miles Cameron
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Jose Gilberto Trevino
- Department of Surgery, University of Florida Health Sciences Center, Gainesville, Florida 32610, United States
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Zhai W, Li S, Zhang J, Chen Y, Ma J, Kong W, Gong D, Zheng J, Xue W, Xu Y. Sunitinib-suppressed miR-452-5p facilitates renal cancer cell invasion and metastasis through modulating SMAD4/SMAD7 signals. Mol Cancer 2018; 17:157. [PMID: 30419914 PMCID: PMC6231268 DOI: 10.1186/s12943-018-0906-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 10/15/2018] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Although microRNAs (miRNAs) were revealed as crucial modulators in tumor metastasis and target therapy, our understanding of their roles in metastatic renal cell carcinoma (mRCC) and Sunitinib treatment was limited. Here we sought to identify human miRNAs that acted as key regulators in renal cancer metastasis and Sunitinib treatment. EXPERIMENTAL DESIGN We focused on 2 published microarray data to select out our anchored miRNA and then explored the roles of miR-452-5p both in vitro and in vivo, which was downregulated after Sunitinib treatment while upregulated in metastasis renal cell carcinoma (RCC) tissues. RESULTS Here, we discovered that treating with Sunitinib, the targeted receptor tyrosine kinase inhibitor (TKI), inhibited renal cancer cell migration and invasion via attenuating the expression of miR-452-5p. The novel identified miR-452-5p was upregulated and associated with poor prognosis in RCC. Preclinical studies using multiple RCC cells and xenografts model illustrated that miR-452-5p could promote RCC cell migration and invasion in vitro and in vivo. Mechanistically, P65 could directly bind to the miR-452-5p promoter and thus transcriptionally induce miR-452-5p expression, which led to post-transcriptionally abrogate SMAD4 expression, thus inhibition of its downstream gene SMAD7. CONCLUSION Our study presented a road map for targeting this newly identified miR-452-5p and its SMAD4/SMAD7 signals pathway, which imparted a new potential therapeutic strategy for mRCC treatment.
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Affiliation(s)
- Wei Zhai
- Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, 160 Pujian Road, Pudong District, Shanghai, 200127, China.
| | - Saiyang Li
- Department of Urology, Shanghai Tenth People's Hospital, Nanjing Medical University, Nanjing, 211166, China
| | - Jin Zhang
- Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, 160 Pujian Road, Pudong District, Shanghai, 200127, China
| | - Yonghui Chen
- Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, 160 Pujian Road, Pudong District, Shanghai, 200127, China
| | - Junjie Ma
- Department of Urology, Shanghai Tenth People's Hospital, Nanjing Medical University, Nanjing, 211166, China
| | - Wen Kong
- Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, 160 Pujian Road, Pudong District, Shanghai, 200127, China
| | - Dongkui Gong
- Department of Urology, Shanghai Tenth People's Hospital, School of Medicine in Tongji University, Shanghai, 200072, China
| | - Junhua Zheng
- Department of Urology, Shanghai First People's Hospital, School of Medicine in Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Wei Xue
- Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, 160 Pujian Road, Pudong District, Shanghai, 200127, China.
| | - Yunfei Xu
- Department of Urology, Shanghai Tenth People's Hospital, School of Medicine in Tongji University, Shanghai, 200072, China.
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Targeting Tumor Metabolism With Statins During Treatment for Advanced-stage Pancreatic Cancer. Am J Clin Oncol 2018; 41:1125-1131. [PMID: 29509593 DOI: 10.1097/coc.0000000000000433] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION A growing body of preclinical data suggests that statins may exert potent antitumor effects, yet the interactions of these medications with standard therapies and clinical outcomes in this population is less clear. We assessed the impact of statin use on outcomes in patients with advanced-stage pancreatic adenocarcinoma undergoing various treatments. MATERIALS AND METHODS After institutional review board approval, we conducted a retrospective-cohort study consisting of 303 newly diagnosed advanced-stage pancreatic adenocarcinoma patients to determine the impact of statin use on outcomes. Univariate and multivariable Cox proportional hazard regression models were utilized to estimate hazard ratios (HRs). Time-to-event was estimated using Kaplan-Meier survival analysis for overall survival, distant metastasis, and locoregional failure. Baseline and active statin usage were assessed and to mitigate risk of immortal time bias, subanalysis excluding patients with under 6 months of follow-up was conducted. RESULTS Both prior (P=0.021) and active (P=0.030) statin usage correlated with improved survival in this cohort. Surgery, chemoradiation, and statin use improved 2-year survival rates (84.1% vs. 55.0%; P<0.001). On multivariable analysis, statin exposure was associated with overall survival (HR, 0.662; P=0.027) and trended to significance for freedom from distant metastasis (HR, 0.577; P=0.060). Comorbid conditions were not significantly associated with outcomes. CONCLUSIONS Statin use was associated with improved overall survival in advanced-stage pancreatic adenocarcinoma patients. This data supports previous findings in early-stage pancreatic adenocarcinoma and other cancer sites. To our knowledge this is the first report to examine the efficacy of statin use as a supplementary treatment option in advanced-stage pancreatic adenocarcinoma patients.
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