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Fang Y, Tan C, Zheng Z, Yang J, Tang J, Guo R, Silli EK, Chen Z, Chen J, Ge R, Liu Y, Wen X, Liang J, Zhu Y, Jin Y, Li Q, Wang Y. The function of microRNA related to cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Biochem Pharmacol 2025; 236:116849. [PMID: 40056941 DOI: 10.1016/j.bcp.2025.116849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/13/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.
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Affiliation(s)
- Yaohui Fang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Chunlu Tan
- Department of Pancreatic Surgery and General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhenjiang Zheng
- Department of Pancreatic Surgery and General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jianchen Yang
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - Jiali Tang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ruizhe Guo
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Epiphane K Silli
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Zhe Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Jia Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ruyu Ge
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yuquan Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiuqi Wen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Jingdan Liang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yunfei Zhu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yutong Jin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Qian Li
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ying Wang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
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2
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Sigirli S, Karakas D. Fibrotic Fortresses and Therapeutic Frontiers: Pancreatic Stellate Cells and the Extracellular Matrix in Pancreatic Cancer. Cancer Med 2025; 14:e70788. [PMID: 40437741 PMCID: PMC12119906 DOI: 10.1002/cam4.70788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/19/2025] [Accepted: 03/08/2025] [Indexed: 06/01/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is characterized by a unique tumor microenvironment (TME) that plays pivotal roles in cancer progression, angiogenesis, metastasis, and drug resistance. This complex and dynamic ecosystem comprises cancer cells, stromal cells, and extracellular matrix (ECM) components, which interact synergistically to drive cancer aggressiveness. Among the stromal cells, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs), mainly accepted as a group of CAFs, are central players in shaping the desmoplastic, hypoxic, and immunosuppressive stroma of PDAC. PSCs, the most abundant stromal cells in PDAC, are resident pancreatic cells that undergo phenotypic changes upon activation, driving tumor progression through the secretion of cytokines, growth factors, ECM components (e.g., collagen, hyaluronic acid, fibronectin), and matrix metalloproteinases. In addition to cellular elements, ECM components significantly contribute to cancer aggressiveness by forming a physical barrier that hinders drug penetration, activating signaling pathways through specific receptor interactions, and generating peptides originating from the fragmentation of proteins to induce cancer migration. Regarding their critical roles in tumor progression, therapeutic approaches targeting PSCs and the ECM have garnered increasing interest in recent years. However, PSCs and stromal components may exhibit dual roles, with the potential to both promote and suppress tumor progression under different conditions. Therefore, targeting PSCs or stroma may lead to unintended outcomes, including exacerbation of cancer aggressiveness. METHODS This review focuses on the multifaceted roles of PSCs in PDAC, particularly their interactions with cancer cells and their contributions to therapy resistance. Additionally, we discuss current and emerging therapeutic strategies targeting PSCs and the ECM components, including both preclinical and clinical efforts. CONCLUSION By synthesizing insights from recent literature, this review provides a comprehensive understanding of the role of PSCs in PDAC pathobiology and highlights potential therapeutic approaches targeting PSCs or ECM components to improve patient outcomes.
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Affiliation(s)
- Sila Sigirli
- Medical Biotechnology, Graduate School of HealthAcibadem Mehmet Ali Aydinlar UniversityIstanbulTurkiye
| | - Didem Karakas
- Medical Biotechnology, Graduate School of HealthAcibadem Mehmet Ali Aydinlar UniversityIstanbulTurkiye
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3
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Acimovic I, Gabrielová V, Martínková S, Eid M, Vlažný J, Moravčík P, Hlavsa J, Moráň L, Cakmakci RC, Staňo P, Procházka V, Kala Z, Trnka J, Vaňhara P. Ex-Vivo 3D Cellular Models of Pancreatic Ductal Adenocarcinoma: From Embryonic Development to Precision Oncology. Pancreas 2025; 54:e57-e71. [PMID: 39074056 DOI: 10.1097/mpa.0000000000002393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
Abstract
ABSTRACT Pancreas is a vital gland of gastrointestinal system with exocrine and endocrine secretory functions, interweaved into essential metabolic circuitries of the human body. Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies, with a 5-year survival rate of 11%. This poor prognosis is primarily attributed to the absence of early symptoms, rapid metastatic dissemination, and the limited efficacy of current therapeutic interventions. Despite recent advancements in understanding the etiopathogenesis and treatment of PDAC, there remains a pressing need for improved individualized models, identification of novel molecular targets, and development of unbiased predictors of disease progression. Here we aim to explore the concept of precision medicine utilizing 3-dimensional, patient-specific cellular models of pancreatic tumors and discuss their potential applications in uncovering novel druggable molecular targets and predicting clinical parameters for individual patients.
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Affiliation(s)
- Ivana Acimovic
- From the Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno
| | - Viktorie Gabrielová
- From the Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno
| | - Stanislava Martínková
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague
| | - Michal Eid
- Departments of Internal Medicine, Hematology and Oncology
| | | | - Petr Moravčík
- Surgery Clinic, University Hospital Brno, Faculty of Medicine, Masaryk University
| | - Jan Hlavsa
- Surgery Clinic, University Hospital Brno, Faculty of Medicine, Masaryk University
| | | | - Riza Can Cakmakci
- From the Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno
| | - Peter Staňo
- Departments of Internal Medicine, Hematology and Oncology
| | - Vladimír Procházka
- Surgery Clinic, University Hospital Brno, Faculty of Medicine, Masaryk University
| | - Zdeněk Kala
- Surgery Clinic, University Hospital Brno, Faculty of Medicine, Masaryk University
| | - Jan Trnka
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague
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Wang H, Qi L, Han H, Li X, Han M, Xing L, Li L, Jiang H. Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies. Acta Pharm Sin B 2024; 14:4756-4775. [PMID: 39664424 PMCID: PMC11628839 DOI: 10.1016/j.apsb.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.
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Affiliation(s)
- Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Han Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Xuena Li
- College of Pharmacy, Yanbian University, Yanji 133000, China
| | - Mengmeng Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing 210009, China
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hulin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- College of Pharmacy, Yanbian University, Yanji 133000, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
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5
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Noda K, Sato Y, Okada Y, Nishida K, Kawano Y, Tanahashi T, Bando M, Okamoto K, Takehara M, Sogabe M, Miyamoto H, Daizumoto K, Kanayama H, Takayama T. Exosomal miR-199a-3p Secreted From Cancer-Associated Adipocytes Promotes Pancreatic Cancer Progression. Cancer Med 2024; 13:e70265. [PMID: 39431622 PMCID: PMC11492146 DOI: 10.1002/cam4.70265] [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: 09/04/2023] [Revised: 06/06/2024] [Accepted: 06/13/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer-associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression. METHODS CAAs were generated by co-culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA-conditioned medium (CAA-CM). Small RNA-seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real-time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC. RESULTS miR-199a-3p expression was significantly increased in CAA-CM-derived exosomes. CAA-derived exosomes transferred miR-199a-3p to pancreatic cancer cells. Transfection with miR-199a-3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR-199a-3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR-199a-3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR-199a is an independent prognostic factor for PDAC. CONCLUSION miR-199a-3p in CAA-derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC.
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Affiliation(s)
- Kazuyoshi Noda
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Yasuyuki Okada
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Kensei Nishida
- Department of PathophysiologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Yutaka Kawano
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Toshihito Tanahashi
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Masahiro Bando
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Koichi Okamoto
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Masanori Takehara
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Masahiro Sogabe
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Kei Daizumoto
- Department of UrologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Hiroomi Kanayama
- Department of UrologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Tetsuji Takayama
- Department of Gastroenterology and OncologyTokushima University Graduate School of Biomedical SciencesTokushimaJapan
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Rebelo R, Xavier CPR, Giovannetti E, Vasconcelos MH. Fibroblasts in pancreatic cancer: molecular and clinical perspectives. Trends Mol Med 2023; 29:439-453. [PMID: 37100646 DOI: 10.1016/j.molmed.2023.03.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 04/28/2023]
Abstract
Pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) are highly abundant cells in the pancreatic tumor microenvironment (TME) that modulate desmoplasia. The formation of a dense stroma leads to immunosuppression and therapy resistance that are major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that several subpopulations of CAFs in the TME can interconvert, explaining the dual roles (antitumorigenic and protumorigenic) of CAFs in PDAC and the contradictory results of CAF-targeted therapies in clinical trials. This highlights the need to clarify CAF heterogeneity and their interactions with PDAC cells. This review focuses on the communication between activated PSCs/CAFs and PDAC cells, as well as on the mechanisms underlying this crosstalk. CAF-focused therapies and emerging biomarkers are also outlined.
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Affiliation(s)
- Rita Rebelo
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal; Department of Biological Sciences, Faculty of Pharmacy of the University of Porto (FFUP), Porto, Portugal
| | - Cristina P R Xavier
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Fondazione Pisana per La Scienza, Pisa, Italy
| | - M Helena Vasconcelos
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-135 Porto, Portugal; Department of Biological Sciences, Faculty of Pharmacy of the University of Porto (FFUP), Porto, Portugal.
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Priwitaningrum DL, Pednekar K, Gabriël AV, Varela-Moreira AA, Le Gac S, Vellekoop I, Storm G, Hennink WE, Prakash J. Evaluation of paclitaxel-loaded polymeric nanoparticles in 3D tumor model: impact of tumor stroma on penetration and efficacy. Drug Deliv Transl Res 2023; 13:1470-1483. [PMID: 36853438 PMCID: PMC10102101 DOI: 10.1007/s13346-023-01310-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2023] [Indexed: 03/01/2023]
Abstract
Since tumor stroma poses as a barrier to achieve efficacy of nanomedicines, it is essential to evaluate nano-chemotherapeutics in stroma-mimicking 3D models that reliably predict their behavior regarding these hurdles limiting efficacy. In this study, we evaluated the effect of paclitaxel-loaded polymeric micelles (PTX-PMCs) and polymeric nanoparticles (PTX-PNPs) in a tumor stroma-mimicking 3D in vitro model. PTX-PMCs (77 nm) based on a amphiphilic block copolymer of mPEG-b-p(HPMAm-Bz) and PTX-PNPs (159 nm) based on poly(lactic-co-glycolic acid) were prepared, which had an encapsulation efficiency (EE%) of 81 ± 15% and 45 ± 8%, respectively. 3D homospheroids of mouse 4T1 breast cancer cells and heterospheroids of NIH3T3 fibroblasts and 4T1 (5:1 ratio) were prepared and characterized with high content two-photon microscopy and immunostaining. Data showed an induction of epithelial-mesenchymal transition (α-SMA) in both homo- and heterospheroids, while ECM (collagen) deposition only in heterospheroids. Two-photon imaging revealed that both fluorescently labeled PMCs and PNPs penetrated into the core of homospheroids and only PMCs penetrated into heterospheroids. Furthermore, PTX-PMCs, PTX-PNPs, and free PTX induced cytotoxicity in tumor cells and fibroblasts grown as monolayer, but these effects were substantially reduced in 3D models, in particular in heterospheroids. Gene expression analysis showed that heterospheroids had a significant increase of drug resistance markers (Bcl2, Abgc2) compared to 2D or 3D monocultures. Altogether, this study shows that the efficacy of nanotherapeutics is challenged by stroma-induced poor penetration and development of resistant phenotype. Therefore, this tumor stroma-mimicking 3D model can provide an excellent platform to study penetration and effects of nanotherapeutics before in vivo studies.
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Affiliation(s)
- Dwi L Priwitaningrum
- Engineered Therapeutics, Department of Advanced Organ Bioengineering and Therapeutics, TechMed Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7500AE, Enschede, The Netherlands
- Department of Pharmaceutics, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Kunal Pednekar
- Engineered Therapeutics, Department of Advanced Organ Bioengineering and Therapeutics, TechMed Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7500AE, Enschede, The Netherlands
| | - Alexandros V Gabriël
- Engineered Therapeutics, Department of Advanced Organ Bioengineering and Therapeutics, TechMed Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7500AE, Enschede, The Netherlands
| | - Aida A Varela-Moreira
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Severine Le Gac
- Applied Microfluidics for BioEngineering Research, Faculty of Electrical Engineering, Mathematics and Computer Science, MESA+ Institute for Nanotechnology, TechMed Centre, University of Twente, Enschede, The Netherlands
| | - Ivo Vellekoop
- Biomedical Photonic Imaging, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Gert Storm
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Wim E Hennink
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Jai Prakash
- Engineered Therapeutics, Department of Advanced Organ Bioengineering and Therapeutics, TechMed Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7500AE, Enschede, The Netherlands.
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8
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Orso F, Virga F, Dettori D, Dalmasso A, Paradzik M, Savino A, Pomatto MAC, Quirico L, Cucinelli S, Coco M, Mareschi K, Fagioli F, Salmena L, Camussi G, Provero P, Poli V, Mazzone M, Pandolfi PP, Taverna D. Stroma-derived miR-214 coordinates tumor dissemination. J Exp Clin Cancer Res 2023; 42:20. [PMID: 36639824 PMCID: PMC9837925 DOI: 10.1186/s13046-022-02553-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 11/29/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Tumor progression is based on a close interaction between cancer cells and Tumor MicroEnvironment (TME). Here, we focus on the role that Cancer Associated Fibroblasts (CAFs), Mesenchymal Stem Cells (MSCs) and microRNAs (miRs) play in breast cancer and melanoma malignancy. METHODS We used public databases to investigate miR-214 expression in the stroma compartment of primary human samples and evaluated tumor formation and dissemination following tumor cell injections in miR-214 overexpressing (miR-214over) and knock out (miR-214ko) mice. In addition, we dissected the impact of Conditioned Medium (CM) or Extracellular Vesicles (EVs) derived from miR-214-rich or depleted stroma cells on cell metastatic traits. RESULTS We evidence that the expression of miR-214 in human cancer or metastasis samples mostly correlates with stroma components and, in particular, with CAFs and MSCs. We present data revealing that the injection of tumor cells in miR-214over mice leads to increased extravasation and metastasis formation. In line, treatment of cancer cells with CM or EVs derived from miR-214-enriched stroma cells potentiate cancer cell migration/invasion in vitro. Conversely, dissemination from tumors grown in miR-214ko mice is impaired and metastatic traits significantly decreased when CM or EVs from miR-214-depleted stroma cells are used to treat cells in culture. Instead, extravasation and metastasis formation are fully re-established when miR-214ko mice are pretreated with miR-214-rich EVs of stroma origin. Mechanistically, we also show that tumor cells are able to induce miR-214 production in stroma cells, following the activation of IL-6/STAT3 signaling, which is then released via EVs subsequently up-taken by cancer cells. Here, a miR-214-dependent pro-metastatic program becomes activated. CONCLUSIONS Our findings highlight the relevance of stroma-derived miR-214 and its release in EVs for tumor dissemination, which paves the way for miR-214-based therapeutic interventions targeting not only tumor cells but also the TME.
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Affiliation(s)
- Francesca Orso
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
- Dept. of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara, Italy
| | - Federico Virga
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
- Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Louvain, Belgium
- Present Address: Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Daniela Dettori
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Alberto Dalmasso
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Mladen Paradzik
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Aurora Savino
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | | | - Lorena Quirico
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Stefania Cucinelli
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Martina Coco
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Katia Mareschi
- Paediatric Onco-Haematology Division, Regina Margherita Children's Hospital, City of Health and Science of Turin, Turin, Italy
- Department of Public Health and Paediatrics, University of Turin, Turin, Italy
| | - Franca Fagioli
- Paediatric Onco-Haematology Division, Regina Margherita Children's Hospital, City of Health and Science of Turin, Turin, Italy
- Department of Public Health and Paediatrics, University of Turin, Turin, Italy
| | - Leonardo Salmena
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Paolo Provero
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Department of Neurosciences "Rita Levi Montalcini", University of Turin, Turin, Italy
| | - Valeria Poli
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy
| | - Massimiliano Mazzone
- Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Louvain, Belgium
| | - Pier Paolo Pandolfi
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy.
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy.
- William N. Pennington Cancer Institute, Renown Health, Nevada System of Higher Education, Reno, NV, 89502, USA.
| | - Daniela Taverna
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy.
- Dept. Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza, 52, 10126, Turin, Italy.
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9
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Ruiz-Llorente L, Ruiz-Rodríguez MJ, Savini C, González-Muñoz T, Riveiro-Falkenbach E, Rodríguez-Peralto JL, Peinado H, Bernabeu C. Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1408:253-272. [PMID: 37093432 DOI: 10.1007/978-3-031-26163-3_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Endoglin (CD105) is an auxiliary receptor of transforming growth factor (TGF)-β family members that is expressed in human melanomas. It is heterogeneously expressed by primary and metastatic melanoma cells, and endoglin targeting as a therapeutic strategy for melanoma tumors is currently been explored. However, its involvement in tumor development and malignancy is not fully understood. Here, we find that endoglin expression correlates with malignancy of primary melanomas and cultured melanoma cell lines. Next, we have analyzed the effect of ectopic endoglin expression on two miRNAs (hsa-mir-214 and hsa-mir-370), both involved in melanoma tumor progression and endoglin regulation. We show that compared with control cells, overexpression of endoglin in the WM-164 melanoma cell line induces; (i) a significant increase of hsa-mir-214 levels in small extracellular vesicles (EVs) as well as an increased trend in cells; and (ii) significantly lower levels of hsa-mir-370 in the EVs fractions, whereas no significant differences were found in cells. As hsa-mir-214 and hsa-mir-370 are not just involved in melanoma tumor progression, but they can also target endoglin-expressing endothelial cells in the tumor vasculature, these results suggest a complex and differential regulatory mechanism involving the intracellular and extracellular signaling of hsa-mir-214 and hsa-mir-370 in melanoma development and progression.
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Affiliation(s)
- Lidia Ruiz-Llorente
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain.
- Biochemistry and Molecular Biology Unit, Department of System Biology, School of Medicine and Health Sciences, University of Alcalá, 28871, Alcalá de Henares, Madrid, Spain.
| | - María Jesús Ruiz-Rodríguez
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain
| | - Claudia Savini
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain
| | - Teresa González-Muñoz
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain
| | - Erica Riveiro-Falkenbach
- Department of Pathology, Instituto i+12, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain
| | - José L Rodríguez-Peralto
- Department of Pathology, Instituto i+12, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain
| | - Héctor Peinado
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
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10
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Septembre-Malaterre A, Boina C, Douanier A, Gasque P. Deciphering the Antifibrotic Property of Metformin. Cells 2022; 11:cells11244090. [PMID: 36552855 PMCID: PMC9777391 DOI: 10.3390/cells11244090] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Fibrosis is a chronic progressive and incurable disease leading to organ dysfunction. It is characterized by the accumulation of extracellular matrix proteins produced by mesenchymal stem cells (MSCs) differentiating into myofibroblasts. Given the complexity of its pathophysiology, the search for effective treatments for fibrosis is of paramount importance. Metformin, a structural dimethyl analog of the galegine guanide extracted from the "French Lilac" (Fabaceae Galega officinalis), is the most widely used antidiabetic drug, recently recognized for its antifibrotic effects through ill-characterized mechanisms. The in vitro model of TGF-β1-induced fibrosis in human primary pulmonary mesenchymal stem cells (HPMSCs), identified as CD248+ and CD90+ cells, was used to study the effects of metformin extracts. These effects were tested on the expression of canonical MSC differentiation markers, immune/inflammatory factors and antioxidative stress molecules using qRT-PCR (mRNA, miRNA), immunofluorescence and ELISA experiments. Interestingly, metformin is able to reduce/modulate the expression of different actors involved in fibrosis. Indeed, TGF-β1 effects were markedly attenuated by metformin, as evidenced by reduced expression of three collagen types and Acta2 mRNAs. Furthermore, metformin attenuated the effects of TGF-β1 on the expression of PDGF, VEGF, erythropoietin, calcitonin and profibrotic miRs, possibly by controlling the expression of several key TGF/Smad factors. The expression of four major fibrogenic MMPs was also reduced by metformin treatment. In addition, metformin controlled MSC differentiation into lipofibroblasts and osteoblasts and had the ability to restore redox balance via the Nox4/Nrf2, AMP and Pi3K pathways. Overall, these results show that metformin is a candidate molecule for antifibrotic effect and/or aiming to combat the development of chronic inflammatory diseases worldwide.
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Affiliation(s)
- Axelle Septembre-Malaterre
- Unité de Recherche, EPI ‘Etudes en Pharmaco-Immunologie’, Université de la Réunion, Allée des Topazes, CS11021, 97400 Saint Denis, France
- Laboratoire D’immunologie Clinique et Expérimentale de la Zone de L’océan Indien (LICE-OI), CHU La Réunion Site Félix Guyon Allée des Topazes, CS11021, 97400 Saint Denis, France
- Correspondence:
| | - Chailas Boina
- Unité de Recherche, EPI ‘Etudes en Pharmaco-Immunologie’, Université de la Réunion, Allée des Topazes, CS11021, 97400 Saint Denis, France
- Laboratoire D’immunologie Clinique et Expérimentale de la Zone de L’océan Indien (LICE-OI), CHU La Réunion Site Félix Guyon Allée des Topazes, CS11021, 97400 Saint Denis, France
| | - Audrey Douanier
- Unité de Recherche, EPI ‘Etudes en Pharmaco-Immunologie’, Université de la Réunion, Allée des Topazes, CS11021, 97400 Saint Denis, France
- Laboratoire D’immunologie Clinique et Expérimentale de la Zone de L’océan Indien (LICE-OI), CHU La Réunion Site Félix Guyon Allée des Topazes, CS11021, 97400 Saint Denis, France
| | - Philippe Gasque
- Unité de Recherche, EPI ‘Etudes en Pharmaco-Immunologie’, Université de la Réunion, Allée des Topazes, CS11021, 97400 Saint Denis, France
- Laboratoire D’immunologie Clinique et Expérimentale de la Zone de L’océan Indien (LICE-OI), CHU La Réunion Site Félix Guyon Allée des Topazes, CS11021, 97400 Saint Denis, France
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11
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Chu X, Yang Y, Tian X. Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs. Int J Mol Sci 2022; 23:ijms23179512. [PMID: 36076911 PMCID: PMC9455258 DOI: 10.3390/ijms23179512] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tumors, characterized by a low rate of early diagnosis, strong invasiveness, and early metastasis. The abundant stromal cells, dense extracellular matrix, and lack of blood supply in PDAC limit the penetration of chemotherapeutic drugs, resulting in poor efficacy of the current treatment regimens. Cancer-associated fibroblasts (CAFs) are the major stromal cells in the tumor microenvironment. Tumor cells can secrete exosomes to promote the generation of activated CAFs, meanwhile exosomes secreted by CAFs help promote tumor progression. The aberrant expression of miRNAs in exosomes is involved in the interaction between tumor cells and CAFs, which provides the possibility for the application of exosomal miRNAs in the diagnosis and treatment of PDAC. The current article reviews the mechanism of exosomal miRNAs in the crosstalk between PDAC cells and CAFs in the tumor microenvironment, in order to improve the understanding of TME regulation and provide evidence for designing diagnostic and therapeutic targets against exosome miRNA in human PDAC.
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12
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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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13
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Liu L, Kshirsagar PG, Gautam SK, Gulati M, Wafa EI, Christiansen JC, White BM, Mallapragada SK, Wannemuehler MJ, Kumar S, Solheim JC, Batra SK, Salem AK, Narasimhan B, Jain M. Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies. Theranostics 2022; 12:1030-1060. [PMID: 35154473 PMCID: PMC8771545 DOI: 10.7150/thno.64805] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 12/03/2021] [Indexed: 01/28/2023] Open
Abstract
Pancreatic tumors are highly desmoplastic and immunosuppressive. Delivery and distribution of drugs within pancreatic tumors are compromised due to intrinsic physical and biochemical stresses that lead to increased interstitial fluid pressure, vascular compression, and hypoxia. Immunotherapy-based approaches, including therapeutic vaccines, immune checkpoint inhibition, CAR-T cell therapy, and adoptive T cell therapies, are challenged by an immunosuppressive tumor microenvironment. Together, extensive fibrosis and immunosuppression present major challenges to developing treatments for pancreatic cancer. In this context, nanoparticles have been extensively studied as delivery platforms and adjuvants for cancer and other disease therapies. Recent advances in nanotechnology have led to the development of multiple nanocarrier-based formulations that not only improve drug delivery but also enhance immunotherapy-based approaches for pancreatic cancer. This review discusses and critically analyzes the novel nanoscale strategies that have been used for drug delivery and immunomodulation to improve treatment efficacy, including newly emerging immunotherapy-based approaches. This review also presents important perspectives on future research directions that will guide the rational design of novel and robust nanoscale platforms to treat pancreatic tumors, particularly with respect to targeted therapies and immunotherapies. These insights will inform the next generation of clinical treatments to help patients manage this debilitating disease and enhance survival rates.
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Affiliation(s)
- Luman Liu
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA
| | - Prakash G. Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
| | - Shailendra K. Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
| | - Mansi Gulati
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
| | - Emad I. Wafa
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA
| | - John C. Christiansen
- Department of Veterinary Microbiology & Preventive Medicine, Iowa State University, Ames, IA
| | - Brianna M. White
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA
| | - Surya K. Mallapragada
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA
- Nanovaccine Institute, Iowa State University, Ames, IA
| | - Michael J. Wannemuehler
- Department of Veterinary Microbiology & Preventive Medicine, Iowa State University, Ames, IA
- Nanovaccine Institute, Iowa State University, Ames, IA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
| | - Joyce C. Solheim
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
- Nanovaccine Institute, Iowa State University, Ames, IA
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha NE
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
- Nanovaccine Institute, Iowa State University, Ames, IA
- Eppley Institute, University of Nebraska Medical Center, Omaha, NE
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha NE
| | - Aliasger K. Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA
- Nanovaccine Institute, Iowa State University, Ames, IA
| | - Balaji Narasimhan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA
- Nanovaccine Institute, Iowa State University, Ames, IA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE
- Nanovaccine Institute, Iowa State University, Ames, IA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha NE
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14
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Hrabák P, Kalousová M, Krechler T, Zima T. Pancreatic stellate cells - rising stars in pancreatic pathologies. Physiol Res 2021. [DOI: 10.33549//physiolres.934783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Pluripotent pancreatic stellate cells (PSCs) receive growing interest in past decades. Two types of PSCs are recognized –vitamin A accumulating quiescent PSCs and activated PSCs- the main producents of extracellular matrix in pancreatic tissue. PSCs plays important role in pathogenesis of pancreatic fibrosis in pancreatic cancer and chronic pancreatitis. PSCs are intensively studied as potential therapeutical target because of their important role in developing desmoplastic stroma in pancreatic cancer. There also exists evidence that PSC are involved in other pathologies like type-2 diabetes mellitus. This article brings brief characteristics of PSCs and recent advances in research of these cells.
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Affiliation(s)
| | - M Kalousová
- 2Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.
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15
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Lu T, Prakash J. Nanomedicine Strategies to Enhance Tumor Drug Penetration in Pancreatic Cancer. Int J Nanomedicine 2021; 16:6313-6328. [PMID: 34552327 PMCID: PMC8450289 DOI: 10.2147/ijn.s279192] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show a desired anticancer effect in vitro; however, very poor efficacy in vivo because of the limited drug delivery and penetration into pancreatic tumors attributed to the abundance of the tumor stroma, ie, the fibrotic tumor microenvironment surrounding the cancer cells. For a better understanding of the challenges posed by the pancreatic tumor stroma, we outline the key features of the tumor microenvironment. Then we highlight major strategies used to tackle the challenges to improve drug penetration into the tumor and achieve enhanced efficacy (pre)clinically. Furthermore, we describe nanomedicine strategies to modulate the tumor stroma, degrade the extracellular matrix, and co-deliver multi-functional drugs, to improve the chemotherapeutics delivery and penetration into pancreatic tumors.
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Affiliation(s)
- Tao Lu
- Engineered Therapeutics Group, Department of Biomaterials Science and Technology, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- Engineered Therapeutics Group, Department of Biomaterials Science and Technology, University of Twente, Enschede, The Netherlands
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16
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Shatnawi A, Abu Rabe DI, Frigo DE. Roles of the tumor suppressor inhibitor of growth family member 4 (ING4) in cancer. Adv Cancer Res 2021; 152:225-262. [PMID: 34353439 DOI: 10.1016/bs.acr.2021.05.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Inhibitor of growth family member 4 (ING4) is best known as a tumor suppressor that is frequently downregulated, deleted, or mutated in many cancers. ING4 regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, autophagy, invasion, angiogenesis, DNA repair and chromatin remodeling. ING4 alters local chromatin structure by functioning as an epigenetic reader of H3K4 trimethylation histone marks (H3K4Me3) and regulating gene transcription through directing histone acetyltransferase (HAT) and histone deacetylase (HDAC) protein complexes. ING4 may serve as a useful prognostic biomarker for many cancer types and help guide treatment decisions. This review provides an overview of ING4's central functions in gene expression and summarizes current literature on the role of ING4 in cancer and its possible use in therapy.
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Affiliation(s)
- Aymen Shatnawi
- Department of Pharmaceutical and Administrative Sciences, University of Charleston School of Pharmacy, Charleston, WV, United States.
| | - Dina I Abu Rabe
- Integrated Bioscience Program, North Carolina Central University, Durham, NC, United States
| | - Daniel E Frigo
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
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17
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Zhang M, Xian HC, Dai L, Tang YL, Liang XH. MicroRNAs: emerging driver of cancer perineural invasion. Cell Biosci 2021; 11:117. [PMID: 34187567 PMCID: PMC8243427 DOI: 10.1186/s13578-021-00630-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
The perineural invasion (PNI), which refers to tumor cells encroaching on nerve, is a clinical feature frequently occurred in various malignant tumors, and responsible for postoperative recurrence, metastasis and decreased survival. The pathogenesis of PNI switches from 'low-resistance channel' hypothesis to 'mutual attraction' theory between peripheral nerves and tumor cells in perineural niche. Among various molecules in perineural niche, microRNA (miRNA) as an emerging modulator of PNI through generating RNA-induced silencing complex (RISC) to orchestrate oncogene and anti-oncogene has aroused a wide attention. This article systematically reviewed the role of microRNA in PNI, promising to identify new biomarkers and offer cancer therapeutic targets.
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Affiliation(s)
- Mei Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Hong-Chun Xian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Li Dai
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China.
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), No.14, Sec. 3, Renminnan Road, Chengdu, 610041, China.
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18
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Wu Y, Zhang C, Jiang K, Werner J, Bazhin AV, D'Haese JG. The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives. Front Oncol 2021; 10:621937. [PMID: 33520728 PMCID: PMC7841014 DOI: 10.3389/fonc.2020.621937] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.
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Affiliation(s)
- Yang Wu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Chun Zhang
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Kuirong Jiang
- Pancreas Center and Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Jan G D'Haese
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
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19
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Mazurkiewicz J, Simiczyjew A, Dratkiewicz E, Ziętek M, Matkowski R, Nowak D. Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy. Int J Mol Sci 2021; 22:E529. [PMID: 33430277 PMCID: PMC7825728 DOI: 10.3390/ijms22020529] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/29/2020] [Accepted: 01/05/2021] [Indexed: 12/14/2022] Open
Abstract
Malignant melanoma is a highly metastatic type of cancer, which arises frequently from transformed pigment cells and melanocytes as a result of long-term UV radiation exposure. In recent years, the incidence of newly diagnosed melanoma patients reached 5% of all cancer cases. Despite the development of novel targeted therapies directed against melanoma-specific markers, patients' response to treatment is often weak or short-term due to a rapid acquisition of drug resistance. Among the factors affecting therapy effectiveness, elements of the tumor microenvironment play a major role. Melanoma niche encompasses adjacent cells, such as keratinocytes, cancer-associated fibroblasts (CAFs), adipocytes, and immune cells, as well as components of the extracellular matrix and tumor-specific physicochemical properties. In this review, we summarize the current knowledge concerning the influence of cancer-associated cells (keratinocytes, CAFs, adipocytes) on the process of melanomagenesis, tumor progression, invasiveness, and the emergence of drug resistance in melanoma. We also address how melanoma can alter the differentiation and activation status of cells present in the tumor microenvironment. Understanding these complex interactions between malignant and cancer-associated cells could improve the development of effective antitumor therapeutic strategies.
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Affiliation(s)
- Justyna Mazurkiewicz
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland; (A.S.); (E.D.); (D.N.)
| | - Aleksandra Simiczyjew
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland; (A.S.); (E.D.); (D.N.)
| | - Ewelina Dratkiewicz
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland; (A.S.); (E.D.); (D.N.)
| | - Marcin Ziętek
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Plac Hirszfelda 12, 53-413 Wroclaw, Poland; (M.Z.); (R.M.)
- Wroclaw Comprehensive Cancer Center, Plac Hirszfelda 12, 53-413 Wroclaw, Poland
| | - Rafał Matkowski
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Plac Hirszfelda 12, 53-413 Wroclaw, Poland; (M.Z.); (R.M.)
- Wroclaw Comprehensive Cancer Center, Plac Hirszfelda 12, 53-413 Wroclaw, Poland
| | - Dorota Nowak
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland; (A.S.); (E.D.); (D.N.)
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Sabouri E, Rajabzadeh A, Enderami SE, Saburi E, Soleimanifar F, Barati G, Rahmati M, Khamisipour G, Enderami SE. The Role of MicroRNAs in the Induction of Pancreatic Differentiation. Curr Stem Cell Res Ther 2021; 16:145-154. [PMID: 32564764 DOI: 10.2174/1574888x15666200621173607] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 04/15/2020] [Accepted: 04/20/2020] [Indexed: 11/22/2022]
Abstract
Stem cell-based therapy is one of the therapeutic options with promising results in the treatment of diabetes. Stem cells from various sources are expanded and induced to generate the cells capable of secreting insulin. These insulin-producing cells [IPCs] could be used as an alternative to islets in the treatment of patients with diabetes. Soluble growth factors, small molecules, geneencoding transcription factors, and microRNAs [miRNAs] are commonly used for the induction of stem cell differentiation. MiRNAs are small non-coding RNAs with 21-23 nucleotides that are involved in the regulation of gene expression by targeting multiple mRNA targets. Studies have shown the dynamic expression of miRNAs during pancreatic development and stem cell differentiation. MiR- 7 and miR-375 are the most abundant miRNAs in pancreatic islet cells and play key roles in pancreatic development as well as islet cell functions. Some studies have tried to use these small RNAs for the induction of pancreatic differentiation. This review focuses on the miRNAs used in the induction of stem cells into IPCs and discusses their functions in pancreatic β-cells.
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Affiliation(s)
- Elham Sabouri
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Rajabzadeh
- Applied Cell Sciences and Tissue Engineering Department, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Elnaz Enderami
- Department of Stem Cell and Regenerative Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology [NIGEB], Tehran, Iran
| | - Ehsan Saburi
- Medical Genetics and Molecular Medicine Department, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Soleimanifar
- Department of Medical Biotechnology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | | | | | - Gholamreza Khamisipour
- Department of Hematology, School of Allied Medical Sciences, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Seyed Ehsan Enderami
- Diabetes Research Center, Department of Medical Biotechnology, Faculty of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Liu AG, Pang YY, Chen G, Wu HY, He RQ, Dang YW, Huang ZG, Zhang R, Ma J, Yang LH. Downregulation of miR-199a-3p in Hepatocellular Carcinoma and Its Relevant Molecular Mechanism via GEO, TCGA Database and In Silico Analyses. Technol Cancer Res Treat 2020; 19:1533033820979670. [PMID: 33327879 PMCID: PMC7750904 DOI: 10.1177/1533033820979670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Existing reports have demonstrated that miR-199a-3p plays a role as a tumor suppressor in a variety of human cancers. This study aims to further validate the expression of miR-199a-3p in HCC and to explore its underlying mechanisms by using multiple data sets. Chip data or sequencing data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were integrated to assess the expression of miR-199a-3p in HCC. The potential targets and transcription factor regulatory network of miR-199a-3p in HCC were determined and possible biological mechanism of miR-199a-3p was analyzed with bioinformatics methods. In the results, miR-199a-3p expression was significantly lower in HCC tissues compared to normal tissues according to chip data or sequencing data and qRT-PCR. Moreover, 455 targets of miR-199a-3p were confirmed, and these genes were involved in the PI3K-Akt signaling pathway, pathways in cancer, and focal adhesions. LAMA4 was considered a key target of miR-199a-3p. In CMTCN, 11 co-regulatory pairs, 3 TF-FFLs, and 2 composite-FFLs were constructed. In conclusion, miR-199a-3p was down regulated in HCC and LAMA4 may be a potential target of miR-199a-3p in HCC.
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Affiliation(s)
- An-Gui Liu
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yu-Yan Pang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hua-Yu Wu
- Departments of Cell Biology and Genetics, School of Pre-clinical Medicine, Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Rong-Quan He
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yi-Wu Dang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhi-Guang Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Rui Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jie Ma
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Li-Hua Yang
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
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Zhang G, Zhai N, Zhang X. Alkannin represses growth of pancreatic cancer cells based on the down regulation of miR-199a. Biofactors 2020; 46:849-859. [PMID: 31967380 DOI: 10.1002/biof.1613] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/27/2019] [Indexed: 01/27/2023]
Abstract
Alkannin displays tumor suppressive activity by initiating apoptosis. Here, we corroborated its role in pancreatic carcinoma (PANC-1) cells and addressed the molecular mechanism in which microRNA-199a (miR-199a) and Klotho might be implicated. PANC-1 and MIN6 cells were treated by alkannin and its role was evaluated in cellular viability. Next we assessed the ability of PANC-1 cells to proliferate, migrate, and invade as well as apoptosis process. Besides, proliferating cell nuclear antigen (PCNA), CyclinD1, p53, and caspases were quantified using Western blot. miR-199a was detected by qRT-PCR. miR-199a-silenced or -replenished cells were established to study its function role in Klotho in conjunction with alkannin. Further, Klotho-overexpressed or -silenced cells were constructed to investigate the alteration of mTOR and MEK/ERK pathways. Alkannin repressed the viability of PANC-1 cells instead of MIN6 cells. Alkannin counteracted the growth of PANC-1 cells through inhibiting proliferation, migration, and invasion and facilitating apoptosis, which was evidenced by the modulation on PCNA, CyclinD1, p53, and cleavage of caspases. The silence of miR-199a by alkannin was also involved in the antitumor process. Alkannin enhanced Klotho expression possibly through silencing miR-199a. Besides, mTOR and MEK/ERK signaling were counteracted by Klotho overexpression while facilitated by its silence. Alkannin inhibited the growth of PANC-1 cells via modulating miR-199a-Klotho node. During this process, mTOR and MEK/ERK pathways were blunted.
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Affiliation(s)
- Guochang Zhang
- Department of Critical Care Medicine, Jining No.1 People's Hospital, Jining, Shandong, China
- Affiliated Jining No. 1 People's Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Nan Zhai
- Department of Critical Care Medicine, Jining No.1 People's Hospital, Jining, Shandong, China
| | - Xiaofen Zhang
- Department of Critical Care Medicine, Jining No.1 People's Hospital, Jining, Shandong, China
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miR-199a-3p suppresses progression of esophageal squamous cell carcinoma through inhibiting mTOR/p70S6K pathway. Anticancer Drugs 2020; 32:157-167. [PMID: 32826415 DOI: 10.1097/cad.0000000000000983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Dysregulation of microRNA contributes to multiple tumorigenic processes. Although downregulation of miR-199a-3p has been shown in many cancers, its effects on esophageal squamous cell carcinoma (ESCC) and the regulatory mechanism are still obscure. Here, we aim to evaluate the biological function and underlying mechanisms of miR-199a-3p in ESCC as well as its value to clinical treatment of ESCC. We first analyzed expression of miR-199a-3p in esophageal cancer by bioinformatic analysis and found that there were different opinions about expression of miR-199a-3p in esophageal cancer, and the following qRT-PCR assay demonstrated which was markedly downregulated in ESCC cells. Next, we increased the expression of miR-199a-3p in ESCC cells using miR-199a-3p mimics and demonstrated that overexpression of miR-199a-3p significantly inhibited cell proliferation, migration and invasion, as well as induced cell cycle retard and promoted apoptosis in ESCC. Furthermore, we explored the functional targets of miR-199a-3p and identified that overexpression of miR-199a-3p inhibited mTOR/p70S6K pathway, but stimulated PI3K/Akt pathway. Finally, we demonstrated that overexpression of miR-199a-3p enhanced proliferation-inhibiting effects of MK2206, an inhibitor of Akt, to ESCC cells, which might be related that MK2206 eliminated the activation of miR-199a-3p to p-Akt. These findings discover that miR-199a-3p might participate in the carcinogenesis process of ESCC, which provides a new insight for treatment of ESCC.
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Okazaki Y, Chew SH, Nagai H, Yamashita Y, Ohara H, Jiang L, Akatsuka S, Takahashi T, Toyokuni S. Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats. Cancer Sci 2020; 111:2016-2027. [PMID: 32248600 PMCID: PMC7293088 DOI: 10.1111/cas.14405] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/17/2020] [Accepted: 03/24/2020] [Indexed: 12/13/2022] Open
Abstract
Malignant mesothelioma (MM) is one of the most lethal tumors in humans. The onset of MM is linked to exposure to asbestos, which generates reactive oxygen species (ROS). ROS are believed to be derived from the frustrated phagocytosis and the iron in asbestos. To explore the pathogenesis of MM, peritoneal MM was induced in rats by the repeated intraperitoneal injection of iron saccharate and nitrilotriacetate. In the present study, we used microarray techniques to screen the microRNA (miR) expression profiles of these MM. We observed that the histological subtype impacted the hierarchical clustering of miR expression profiles and determined that miR-199/214 is a distinctive feature of iron saccharate-induced sarcomatoid mesothelioma (SM). Twist1, a transcriptional regulator of the epithelial-mesenchymal transition, has been shown to activate miR-199/214 transcription; thus, the expression level of Twist1 was examined in iron-induced and asbestos-induced mesotheliomas in rats. Twist1 was exclusively expressed in iron saccharate-induced SM but not in the epithelioid subtype. The Twist1-miR-199/214 axis is activated in iron saccharate-induced and asbestos-induced SM. The expression levels of miR-214 and Twist1 were correlated in an asbestos-induced MM cell line, suggesting that the Twist1-miR-199/214 axis is preserved. MeT5A, an immortalized human mesothelial cell line, was used for the functional analysis of miR. The overexpression of miR-199/214 promoted cellular proliferation, mobility and phosphorylation of Akt and ERK in MeT5A cells. These results indicate that miR-199/214 may affect the aggressive biological behavior of SM.
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Affiliation(s)
- Yasumasa Okazaki
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Shan Hwu Chew
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Hirotaka Nagai
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Yoriko Yamashita
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Hiroki Ohara
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Li Jiang
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Shinya Akatsuka
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
| | - Takashi Takahashi
- Division of Molecular CarcinogenesisNagoya University Graduate School of MedicineNagoyaJapan
- Aichi Cancer Center Research InstituteNagoyaJapan
| | - Shinya Toyokuni
- Department of Pathology and Biological ResponsesNagoya University Graduate School of MedicineNagoyaJapan
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Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment. Cancers (Basel) 2020; 12:cancers12051347. [PMID: 32466266 PMCID: PMC7281461 DOI: 10.3390/cancers12051347] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/12/2020] [Accepted: 05/19/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.
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Kabekkodu SP, Shukla V, Varghese VK, Adiga D, Vethil Jishnu P, Chakrabarty S, Satyamoorthy K. Cluster miRNAs and cancer: Diagnostic, prognostic and therapeutic opportunities. WILEY INTERDISCIPLINARY REVIEWS. RNA 2020; 11:e1563. [PMID: 31436881 DOI: 10.1002/wrna.1563] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 07/05/2019] [Accepted: 07/25/2019] [Indexed: 02/06/2023]
Abstract
MiRNAs are class of noncoding RNA important for gene expression regulation in many plants, animals and viruses. MiRNA clusters contain a set of two or more miRNA encoding genes, transcribed together as polycistronic miRNAs. Currently, there are approximately 159 miRNA clusters reported in the human genome consisting of miRNAs ranging from two or more miRNA genes. A large proportion of clustered miRNAs resides in and around the fragile sites or cancer associated genomic hotspots and plays an important role in carcinogenesis. Altered expression of miRNA cluster can be pro-tumorigenic or anti-tumorigenic and can be targeted for clinical management of cancer. Over the past few years, manipulation of miRNA clusters expression is attempted for experimental purpose as well as for diagnostic, prognostic and therapeutic applications in cancer. Re-expression of miRNAs by epigenetic therapy, genome editing such as clustered regulatory interspaced short palindromic repeats (CRISPR) and miRNA mowers showed promising results in cancer therapy. In this review, we focused on the potential of miRNA clusters as a biomarker for diagnosis, prognosis, targeted therapy as well as strategies for modulating their expression in a therapeutic context. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Processing > Processing of Small RNAs RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.
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Affiliation(s)
- Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vaibhav Shukla
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Vinay Koshy Varghese
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Padacherri Vethil Jishnu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression. Cancers (Basel) 2020; 12:cancers12020324. [PMID: 32019274 PMCID: PMC7072427 DOI: 10.3390/cancers12020324] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of SS18-SSX1 into mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicated SWI/SNF pathway modulation by SS18-SSX1 introduction into mesenchymal cells and Tle1 and Atf2 upregulation in tumors. These findings indicate that the model exhibits phenotypes typical of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites within the Dnm3 locus as the most frequent in 30 mouse synovial sarcomas. miR-199a2 and miR-214 upregulation within the Dnm3 locus was observed. SS18-SSX1 and miR-214 cointroduction accelerated sarcoma onset, indicating that miR-214 is a cooperative oncomiR in synovial sarcomagenesis. miR-214 functions in a cell non-autonomous manner, promoting cytokine gene expression (e.g., Cxcl15/IL8). Our results emphasize the role of miR-214 in tumor development and disease progression.
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28
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Xie Y, Hang Y, Wang Y, Sleightholm R, Prajapati DR, Bader J, Yu A, Tang W, Jaramillo L, Li J, Singh RK, Oupický D. Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy. ACS NANO 2020; 14:255-271. [PMID: 31927946 PMCID: PMC7041410 DOI: 10.1021/acsnano.9b03978] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRASG12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRASG12D, the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.
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Affiliation(s)
- Ying Xie
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Yu Hang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Yazhe Wang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Richard Sleightholm
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Dipakkumar R Prajapati
- Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Johannes Bader
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
- Department of Pharmacy, Pharmaceutical Technology and Biopharmacy , Ludwig-Maximilians-Universität München , 81337 Munich , Germany
| | - Ao Yu
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Weimin Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Lee Jaramillo
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
- Bohemica Pharmaceuticals, LLC , La Vista , Nebraska 68128 , United States
| | - Jing Li
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Rakesh K Singh
- Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - David Oupický
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
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Jin G, Hong W, Guo Y, Bai Y, Chen B. Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer. J Cancer 2020; 11:1505-1515. [PMID: 32047557 PMCID: PMC6995390 DOI: 10.7150/jca.38616] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 12/08/2019] [Indexed: 12/14/2022] Open
Abstract
Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. During tumorigenesis, quiescent PSCs change into an active myofibroblast-like phenotype which could create a favorable tumor microenvironment and facilitate cancer progression by increasing proliferation, invasiveness and inducing treatment resistance of pancreatic cancer cells. Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-β, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-κB (NF-κB) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. In this review, we systematically summarize the current knowledge about PSCs activation-associated stimulating factors and signaling pathways and hope to provide new strategies for the treatment of pancreatic diseases.
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Affiliation(s)
- Guihua Jin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Weilong Hong
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yangyang Guo
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, 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, Wenzhou 325000, China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
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30
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Mardhian DF, Vrynas A, Storm G, Bansal R, Prakash J. FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor. Nanotheranostics 2020; 4:26-39. [PMID: 31911892 PMCID: PMC6940204 DOI: 10.7150/ntno.38092] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 11/22/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), characterized with abundant tumor stroma, is a highly malignant tumor with poor prognosis. The tumor stroma largely consists of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), and is known to promote tumor growth and progression as well as acts as a barrier to chemotherapy. Inhibition of tumor stroma is highly crucial to induce the effect of chemotherapy. In this study, we delivered fibroblast growth factor 2 (FGF2) to human pancreatic stellate cells (hPSCs), the precursors of CAFs, using superparamagnetic iron oxide nanoparticles (SPIONs). FGF2 was covalently conjugated to functionalized PEGylated dextran-coated SPIONs. FGF2-SPIONs significantly reduced TGF-β induced hPSCs differentiation (α-SMA and collagen-1 expression) by inhibiting pSmad2/3 signaling and inducing ERK1/2 activity, as shown with western blot analysis. Then, we established a stroma-rich self-assembling 3D heterospheroid model by co-culturing PANC-1 and hPSCs in 3D environment. We found that FGF2-SPIONs treatment alone inhibited the tumor stroma-induced spheroid growth. In addition, they also potentiated the effect of gemcitabine, as shown by measuring the spheroid size and ATP content. These effects were attributed to the reduced expression of the hPSC activation and differentiation marker, α-SMA. Furthermore, to demonstrate an application of SPIONs, we applied an external magnetic field to spheroids while incubated with FGF2-SPIONs. This resulted in an enhanced effect of gemcitabine in our 3D model. In conclusion, this study presents a novel approach to target FGF2 to tumor stroma using SPIONs and thereby enhancing the effect of gemcitabine as demonstrated in the complex 3D tumor spheroid model.
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Affiliation(s)
- Deby Fajar Mardhian
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands
| | - Aggelos Vrynas
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands
| | - Gert Storm
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands
| | - Ruchi Bansal
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands
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31
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Chen H, Tan P, Qian B, Du Y, Wang A, Shi H, Huang Z, Huang S, Liang T, Fu W. Hic-5 deficiency protects cerulein-induced chronic pancreatitis via down-regulation of the NF-κB (p65)/IL-6 signalling pathway. J Cell Mol Med 2019; 24:1488-1503. [PMID: 31797546 PMCID: PMC6991662 DOI: 10.1111/jcmm.14833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/16/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-κB (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α-SMA and Col1a1. Therefore, we determined whether suppressing NF-κB/p65 alleviated CP by treating mice with the NF-κB/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-κB/p65 inhibition. These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis.
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Affiliation(s)
- Hao Chen
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Peng Tan
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Baolin Qian
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yichao Du
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ankang Wang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hao Shi
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhiwei Huang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shiyao Huang
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tiancheng Liang
- Luzhou Municipal Hospital of Traditional Chinese Medicine, Luzhou, China
| | - Wenguang Fu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
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32
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Savardashtaki A, Shabaninejad Z, Movahedpour A, Sahebnasagh R, Mirzaei H, Hamblin MR. miRNAs derived from cancer-associated fibroblasts in colorectal cancer. Epigenomics 2019; 11:1627-1645. [PMID: 31702390 PMCID: PMC7132634 DOI: 10.2217/epi-2019-0110] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 09/24/2019] [Indexed: 02/07/2023] Open
Abstract
Currently, the incidence of colorectal cancer (CRC) is increasing across the world. The cancer stroma exerts an impact on the spread, invasion and chemoresistance of CRC. The tumor microenvironment involves a complex interaction between cancer cells and stromal cells, for example, cancer-associated fibroblasts (CAFs). CAFs can promote neoplastic angiogenesis and tumor development in CRC. Mounting evidence suggests that many miRNAs are overexpressed (miR-21, miR-329, miR-181a, miR-199a, miR-382 and miR-215) in CRC CAFs, and these miRNAs can influence the spread, invasiveness and chemoresistance in neighboring tumor cells via paracrine signaling. Herein, we summarize the pathogenic roles of miRNAs and CAFs in CRC. Moreover, for first time, we highlight the miRNAs derived from CRC-associated CAFs and their roles in CRC pathogenesis.
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Affiliation(s)
- Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences … Technologies, Shiraz University of Medical Sciences Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Shabaninejad
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences … Technologies, Shiraz University of Medical Sciences Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA
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Tesfaye AA, Azmi AS, Philip PA. miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:58-70. [PMID: 30558723 DOI: 10.1016/j.ajpath.2018.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/20/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would guide therapy. miRNAs are small noncoding RNAs that regulate the expression of some key genes by targeting their 3'-untranslated mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been identified as potential tools for early diagnosis, prediction of treatment response, and prognosis of patients with PDAC. In this review, we present a summary of the miRNAs that have been studied in PDAC in the context of disease biology.
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Affiliation(s)
- Anteneh A Tesfaye
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan
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34
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Kadel D, Zhang Y, Sun HR, Zhao Y, Dong QZ, Qin LX. Current perspectives of cancer-associated fibroblast in therapeutic resistance: potential mechanism and future strategy. Cell Biol Toxicol 2019; 35:407-421. [PMID: 30680600 PMCID: PMC6881418 DOI: 10.1007/s10565-019-09461-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/15/2018] [Accepted: 01/03/2019] [Indexed: 12/18/2022]
Abstract
The goal of cancer eradication has been overshadowed despite the continuous improvement in research and generation of novel cancer therapeutic drugs. One of the undeniable existing problems is drug resistance due to which the paradigm of killing all cancer cells is ineffective. Tumor microenvironment plays a crucial role in inducing drug resistance besides cancer development and progression. Recently, many efforts have been devoted to understand the role of tumor microenvironment in cancer drug resistance as it provides the shelter, nutrition, and paracrine niche for cancer cells. Cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, reside in symbiotic relationship with cancer cells, supporting them to survive from cancer drugs. The present review summarizes the recent understandings in the role of CAFs in drug resistance in various tumors. Acknowledging the fact that drug resistance depends not only upon cancer cells but also upon the microenvironment niche could guide us to formulate novel cancer drugs and provide the optimal cancer treatment.
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Affiliation(s)
- Dhruba Kadel
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Cancer Metastasis institute, Fudan University, Shanghai, 200040, China
| | - Yu Zhang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Cancer Metastasis institute, Fudan University, Shanghai, 200040, China
| | - Hao-Ran Sun
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Cancer Metastasis institute, Fudan University, Shanghai, 200040, China
| | - Yue Zhao
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
- Cancer Metastasis institute, Fudan University, Shanghai, 200040, China
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Cancer Metastasis institute, Fudan University, Shanghai, 200040, China.
- Institute of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Cancer Metastasis institute, Fudan University, Shanghai, 200040, China.
- Institute of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
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35
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Kuninty PR, Bansal R, De Geus SWL, Mardhian DF, Schnittert J, van Baarlen J, Storm G, Bijlsma MF, van Laarhoven HW, Metselaar JM, Kuppen PJK, Vahrmeijer AL, Östman A, Sier CFM, Prakash J. ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. SCIENCE ADVANCES 2019; 5:eaax2770. [PMID: 31517053 PMCID: PMC6726450 DOI: 10.1126/sciadv.aax2770] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 08/05/2019] [Indexed: 05/08/2023]
Abstract
Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.
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Affiliation(s)
- Praneeth R. Kuninty
- Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Ruchi Bansal
- Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | | | - Deby F. Mardhian
- Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Jonas Schnittert
- Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Joop van Baarlen
- Laboratory Pathology Oost Netherlands (LabPON), Hengelo, Netherlands
| | - Gert Storm
- Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
- Department of Pharmaceutics, Utrecht University, Utrecht, Netherlands
| | - Maarten F. Bijlsma
- Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
| | | | - Josbert M. Metselaar
- ScarTec Therapeutics BV, Enschede, Netherlands
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH University Clinic, Forckenbeckstrasse 55, 52074 Aachen, Germany
| | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands
| | | | - Arne Östman
- Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
| | - Cornelis F. M. Sier
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands
| | - Jai Prakash
- Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
- ScarTec Therapeutics BV, Enschede, Netherlands
- Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
- Corresponding author.
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Tang Q, Zheng F, Liu Z, Wu J, Chai X, He C, Li L, Hann SS. Novel reciprocal interaction of lncRNA HOTAIR and miR-214-3p contribute to the solamargine-inhibited PDPK1 gene expression in human lung cancer. J Cell Mol Med 2019; 23:7749-7761. [PMID: 31475459 PMCID: PMC6815775 DOI: 10.1111/jcmm.14649] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 07/12/2019] [Accepted: 08/10/2019] [Indexed: 12/13/2022] Open
Abstract
Solamargine (SM) has been shown to have anti‐cancer properties. However, the underlying mechanism involved remains undetermined. We showed that SM inhibited the growth of non‐small cell lung cancer (NSCLC) cells, which was enhanced in cells with silencing of long non‐coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), while it overcame by overexpression of HOTAIR. In addition, SM increased the expression of miR‐214‐3p and inhibited 3‐phosphoinositide‐dependent protein kinase‐1 (PDPK1) gene expression, which was strengthened by miR‐214‐3p mimics. Intriguingly, HOTAIR could directly bind to miR‐214‐3p and sequestered miR‐214‐3p from the target gene PDPK1. Intriguingly, overexpression of PDPK1 overcame the effects of SM on miR‐214‐3p expressions and neutralized the SM‐inhibited cell growth. Similar results were observed in vivo. In summary, our results showed that SM‐inhibited NSCLC cell growth through the reciprocal interaction between HOTAIR and miR‐214‐3p, which ultimately suppressed PDPK1 gene expression. HOTAIR effectively acted as a competing endogenous RNA (ceRNA) to stimulate the expression of target gene PDPK1. These complex interactions and feedback mechanisms contribute to the overall effect of SM. This unveils a novel molecular mechanism underlying the anti‐cancer effect of SM in human lung cancer.
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Affiliation(s)
- Qing Tang
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fang Zheng
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zheng Liu
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - JingJing Wu
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - XiaoSu Chai
- Department of Medical Oncology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - CuenXa He
- Department of Medical Oncology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liuning Li
- Department of Medical Oncology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Swei Sunny Hann
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
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37
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Farran B, Nagaraju GP. The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets. Cytokine Growth Factor Rev 2019; 48:11-23. [PMID: 31331827 DOI: 10.1016/j.cytogfr.2019.07.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023]
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Scientific reports concerning the impact of interleukin 4, interleukin 10 and transforming growth factor β on cancer cells. Cent Eur J Immunol 2019; 44:190-200. [PMID: 31530989 PMCID: PMC6745546 DOI: 10.5114/ceji.2018.76273] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 03/12/2018] [Indexed: 02/07/2023] Open
Abstract
Cytokines are signalling proteins generated in most part by immune cells that have critical functions in cellular lifespan. Here we present recent data on three selected anti-inflammatory cytokines: interleukin (IL)-10, IL-4 and transforming growth factor β (TGF-β). IL-10 inhibits the synthesis of major pro-inflammatory cytokines, chemokines, and mediates anti-inflammatory reactions. IL-4 is a multifunctional cytokine which plays a crucial role in the regulation of immune responses and is involved in processes associated with development and differentiation of lymphocytes and regulation of T cell survival. Transforming TGF-β, which in normal cells or pre-cancerous cells, promotes proliferation arrest which represses tumour growth. In this review, we focus on the influence of IL-10, IL-4 and TGF-β on various types of cancer as well as potential of these selected cytokines to serve as new biomarkers which can support effective therapies for cancer patients. This article is presented based on a review of the newest research results.
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39
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Li L, Mou YP, Wang YY, Wang HJ, Mou XZ. miR-199a-3p targets ETNK1 to promote invasion and migration in gastric cancer cells and is associated with poor prognosis. Pathol Res Pract 2019; 215:152511. [PMID: 31255331 DOI: 10.1016/j.prp.2019.152511] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/28/2019] [Accepted: 06/20/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE To investigate the prognostic significance of miR-199a-3p and its role in invasion and metastasis in gastric cancer. METHODS miR-199a-3p expression in 436 formalin-fixed and 39 frozen gastric cancer tissues was investigated by in situ hybridization and RT-PCR, respectively. The role of miR-199a-3p in the migration and invasion of gastric cancer cells was determined in overexpression and inhibitor studies using transwell assays and the SGC-7901, BGC-823 and MGC-803 gastric cancer cells lines. The effect of miR-199a-3p expression on ethanolamine kinase 1 (ETNK1) levels was determined by western botting. RESULTS miR-199a-3p was significantly up-regulated in AGS, SGC-7901, BGC-823 and MGC-803 gastric cancer cells, when compared with GES-1 non-malignant gastric epithelial cells. In situ hybridization studies revealed that human non-tumor gastric mucosa samples were negative for miR-199a-3p expression, while 162 of 436 (37.16%) cases of gastric cancer demonstrated positive expression. miR-199a-3p overexpression was associated with tumor size, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage and prognosis. In patients with I, II and III stage tumors, high miR-199a-3p expression was associated with a significantly lower 5-year survival rate. miR-199a-3p overexpression was associated with increased cell migration and invasion. ETNK1 expression was inhibited following miR-199a-3p overexpression in BGC-823 and SGC-7901 cells, and elevated following miR-199a-3p suppression in MGC-803 cells. CONCLUSION miR-199a-3p is highly expressed in gastric cancer, and correlates with invasion, metastasis and prognosis. miR-199a-3p regulates the invasion and migration of gastric cancer cells by targeting ETNK1. Consequently, miR-199a-3p may serve as a prognostic indicator in gastric cancer.
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Affiliation(s)
- Li Li
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, PR China
| | - Yi-Ping Mou
- Departments of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, PR China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, PR China
| | - Yuan-Yu Wang
- Departments of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, PR China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, PR China.
| | - Hui-Ju Wang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, PR China
| | - Xiao-Zhou Mou
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China; Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, 310014, PR China
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40
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Zhang Y, Zhao Z, Li S, Dong L, Li Y, Mao Y, Liang Y, Tao Y, Ma J. Inhibition of miR‑214 attenuates the migration and invasion of triple‑negative breast cancer cells. Mol Med Rep 2019; 19:4035-4042. [PMID: 30942417 PMCID: PMC6471216 DOI: 10.3892/mmr.2019.10112] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 11/21/2018] [Indexed: 12/26/2022] Open
Abstract
Triple‑negative breast cancer (TNBC) is a subtype of breast cancer. MicroRNA (miR)‑214 is closely associated with controlling the development of tumor cells; therefore, in the present study, the target gene and effects of miR‑214 on TNBC cells were explored. Luciferase activity was examined by luciferase reporter assay. The viability, invasion and migration of MDA‑MB‑231 TNBC cells were measured using Cell Counting kit‑8, Transwell and wound‑healing assays, respectively. The expression levels of various factors were determined using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that the expression levels of miR‑214 were higher and the levels of α1‑antitrypsin (α1‑AT) were lower in TNBC tissues compared with in normal tissues. Subsequently, α1‑AT was revealed to be a target of miR‑214. Furthermore, inhibition of miR‑214 decreased cell viability, invasion and migration, enhanced the expression of E‑cadherin and tissue inhibitor of metalloproteinases‑2, and reduced the expression of metastatic tumour antigen 1 and matrix metalloproteinase‑2. Inhibition of miR‑214 also significantly downregulated the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and markedly downregulated that of phosphoinositide 3‑kinase (PI3K); however, the expression levels of total PI3K, Akt and mTOR remained stable in all groups. Taken together, these findings indicated that α1‑AT may be a target of miR‑214. Downregulation of miR‑214 markedly suppressed the viability, migration and invasion of MDA‑MB‑231 cells, and inhibited the PI3K/Akt/mTOR pathway. These findings suggested that miR‑214 targeting α1‑AT may be a potential mechanism underlying TNBC development.
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Affiliation(s)
- Yi Zhang
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Zhijing Zhao
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Siqi Li
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Liying Dong
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Yan Li
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Ying Mao
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Ying Liang
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Yun Tao
- Clinical Skill Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Junfeng Ma
- Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
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Schnittert J, Bansal R, Mardhian DF, van Baarlen J, Östman A, Prakash J. Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer. FASEB J 2019; 33:6609-6621. [PMID: 30808244 DOI: 10.1096/fj.201802336r] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest tumor due to its highly abundant tumor stroma. Pancreatic stellate cells (PSCs) are considered precursor cells of cancer-associated fibroblasts (CAFs), which induce tumor progression, invasion, and metastasis. In this study, we investigated the role of integrin subunit α (ITGA) 11, the receptor for collagen type I, in tumor stroma interaction. Clinical sample analysis showed that ITGA11 was overexpressed by CAFs in PDAC stroma, as shown with colocalization immunostaining with α-smooth muscle actin. In contrast, there was no expression in healthy pancreas. Public transcriptomic data confirmed a reduced expression of ITGA11 in healthy pancreas and adjacent nontumoral tissues compared with human tumor tissues. Primary human PSCs (hPSCs) activated with either TGF-β or pancreatic cancer cell (PANC-1)-conditioned medium (CM) resulted in the significant up-regulation of ITGA11 and various CAF markers. Furthermore, short hairpin RNA (shRNA)-mediated stable ITGA11 knockdown (shITGA11) in hPSCs significantly inhibited TGF-β- and PANC-1 CM-mediated activation at both gene and protein levels of extracellular matrix, cytokines, and adhesion molecules. Additionally, shITGA11 hPSCs had a reduced migration and contractility compared with shRNA control (shCTR) PSCs. Furthermore, we investigated the effect of ITGA11 on the paracrine effects of hPSCs. Interestingly, the CM from shITGA11 hPSCs, activated with either TGF-β or PANC-1 CM, caused tumor cells to migrate and invade lesser compared with their counterpart, activated shCTR PSCs. In summary, this study presents ITGA11 as an interesting stromal therapeutic target that plays a crucial role in the regulation of the differentiation of PSCs into CAFs and paracrine effects.-Schnittert, J., Bansal, R., Mardhian, D. F., van Baarlen, J., Östman, A., Prakash, J. Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer.
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Affiliation(s)
- Jonas Schnittert
- Department of Biomaterials, Science, and Technology, TechMed Centre, Targeted Therapeutics Section, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Ruchi Bansal
- Department of Biomaterials, Science, and Technology, TechMed Centre, Targeted Therapeutics Section, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Deby F Mardhian
- Department of Biomaterials, Science, and Technology, TechMed Centre, Targeted Therapeutics Section, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Joop van Baarlen
- Laboratory Pathology East Netherlands (LabPON), Hengelo, The Netherlands
| | - Arne Östman
- Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden
| | - Jai Prakash
- Department of Biomaterials, Science, and Technology, TechMed Centre, Targeted Therapeutics Section, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.,Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden
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42
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Schnittert J, Bansal R, Prakash J. Targeting Pancreatic Stellate Cells in Cancer. Trends Cancer 2019; 5:128-142. [PMID: 30755305 DOI: 10.1016/j.trecan.2019.01.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/20/2018] [Accepted: 01/03/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic stellate cells (PSCs) are the major contributor to the aggressive, metastatic, and resilient nature of pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis with a 5-year survival rate of 8%. PSCs constitute more than 50% of the tumor stroma in PDAC, where they induce extensive desmoplasia by secreting abundant extracellular matrix (ECM) proteins. In addition, they establish dynamic crosstalk with cancer cells and other stromal cells, which collectively supports tumor progression via various inter- and intracellular pathways. These cellular interactions and associated pathways may reveal novel therapeutic opportunities against this unmet clinical problem. In this review article, we discuss the role of PSCs in inducing tumor progression, their crosstalk with other cells, and therapeutic strategies to target PSCs.
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Affiliation(s)
- Jonas Schnittert
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Ruchi Bansal
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands; ScarTec Therapeutics BV, Enschede, The Netherlands.
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The essential role of tumor suppressor gene ING4 in various human cancers and non-neoplastic disorders. Biosci Rep 2019; 39:BSR20180773. [PMID: 30643005 PMCID: PMC6356015 DOI: 10.1042/bsr20180773] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 12/19/2018] [Accepted: 01/13/2019] [Indexed: 12/21/2022] Open
Abstract
Inhibitor of growth 4 (ING4), a member of the ING family discovered in 2003, has been shown to act as a tumor suppressor and is frequently down-regulated in various human cancers. Numerous published in vivo and in vitro studies have shown that ING4 is responsible for important cancer hallmarks such as pathologic cell cycle arrest, apoptosis, autophagy, contact inhibition, and hypoxic adaptation, and also affects tumor angiogenesis, invasion, and metastasis. These characteristics are typically associated with regulation through chromatin acetylation by binding histone H3 trimethylated at lysine 4 (H3K4me3) and through transcriptional activity of transcription factor P53 and NF-κB. In addition, emerging evidence has indicated that abnormalities in ING4 expression and function play key roles in non-neoplastic disorders. Here, we provide an overview of ING4-modulated chromosome remodeling and transcriptional function, as well as the functional consequences of different genetic variants. We also present the current understanding concerning the role of ING4 in the development of neoplastic and non-neoplastic diseases. These studies offer inspiration for pursuing novel therapeutics for various cancers.
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Hsieh TH, Liu YR, Chang TY, Liang ML, Chen HH, Wang HW, Yen Y, Wong TT. Global DNA methylation analysis reveals miR-214-3p contributes to cisplatin resistance in pediatric intracranial nongerminomatous malignant germ cell tumors. Neuro Oncol 2019; 20:519-530. [PMID: 29036598 DOI: 10.1093/neuonc/nox186] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Pediatric central nervous system germ cell tumors (CNSGCTs) are rare and heterogeneous neoplasms, which can be divided into germinomas and nongerminomatous germ cell tumors (NGGCTs). NGGCTs are further subdivided into mature teratomas and nongerminomatous malignant GCTs (NGMGCTs). Clinical outcomes suggest that NGMGCTs have poor prognosis and survival and that they require more extensive radiotherapy and adjuvant chemotherapy. However, the mechanisms underlying this difference are still unclear. DNA methylation alteration is generally acknowledged to cause therapeutic resistance in cancers. We hypothesized that the pediatric NGMGCTs exhibit a different genome-wide DNA methylation pattern, which is involved in the mechanism of its therapeutic resistance. Methods We performed methylation and hydroxymethylation DNA immunoprecipitation sequencing, mRNA expression microarray, and small RNA sequencing (smRNA-seq) to determine methylation-regulated genes, including microRNAs (miRNAs). Results The expression levels of 97 genes and 8 miRNAs were correlated with promoter DNA methylation and hydroxymethylation status, such as the miR-199/-214 cluster, and treatment with DNA demethylating agent 5-aza-2'-deoxycytidine elevated its expression level. Furthermore, smRNA-seq analysis showed 27 novel miRNA candidates with differential expression between germinomas and NGMGCTs. Overexpresssion of miR-214-3p in NCCIT cells leads to reduced expression of the pro-apoptotic protein BCL2-like 11 and induces cisplatin resistance. Conclusions We interrogated the differential DNA methylation patterns between germinomas and NGMGCTs and proposed a mechanism for chemoresistance in NGMGCTs. In addition, our sequencing data provide a roadmap for further pediatric CNSGCT research and potential targets for the development of new therapeutic strategies.
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Affiliation(s)
- Tsung-Han Hsieh
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.,Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yun-Ru Liu
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.,Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan
| | - Ting-Yu Chang
- Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan.,Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Muh-Lii Liang
- Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital (VGH-TPE), Taipei, Taiwan
| | - Hsin-Hung Chen
- Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital (VGH-TPE), Taipei, Taiwan
| | - Hsei-Wei Wang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Yun Yen
- Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan.,Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Tai-Tong Wong
- Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan.,Institutes of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan
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Regulat-INGs in tumors and diseases: Focus on ncRNAs. Cancer Lett 2019; 447:66-74. [PMID: 30673590 DOI: 10.1016/j.canlet.2019.01.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/21/2018] [Accepted: 01/08/2019] [Indexed: 12/11/2022]
Abstract
ING family genes (Inhibitor of Growth) are tumor suppressor genes that play a vital role in cell homeostasis. It has been shown that their expression is lost or diminished in many cancers and other diseases. The main mechanisms by which they are regulated in oncogenesis have not yet been fully elucidated. The involvement of non-coding RNAs (ncRNAs) and in particular microRNAs (miRNAs) in post-transcriptional gene regulation is well established. miRNAs are short sequences (18-25 nucleotides) that can bind to the 3 'UTR sequence of the targeted messenger RNA (mRNA), leading to its degradation or translational repression. Interactions between the ING family and miRNAs have been described in some cancers but also in other diseases. The involvement of miRNAs in ING family regulation opens up new fields of investigation, particularly for targeted therapies. In this review, we will summarize the regulatory mechanisms at the RNA and protein level of the ING family and focus on the interactions with ncRNAs.
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Pittenger ST, Schaal VL, Moore D, Guda RS, Koul S, Yelamanchili SV, Bevins RA, Pendyala G. MicroRNA cluster miR199a/214 are differentially expressed in female and male rats following nicotine self-administration. Sci Rep 2018; 8:17464. [PMID: 30504847 PMCID: PMC6269448 DOI: 10.1038/s41598-018-35747-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/05/2018] [Indexed: 12/19/2022] Open
Abstract
Previous research has established sex differences associated with nicotine intake, however a significant gap in knowledge remains regarding the molecular mechanisms that govern these differences at the transcriptional level. One critical regulator of transcription are microRNAs (miRNAs). miRNAs are a family of non-coding RNAs that regulate an array of important biological functions altered in several disease states, including neuroadaptive changes within the brain associated with drug dependence. We examined the prefrontal cortex (PFC) from male and female Sprague-Dawley rats following self-administration (22 days) of nicotine or yoked saline controls using next generation RNA-Sequencing (RNA-Seq) technology and found an array of miRNAs to be significantly and differentially regulated by nicotine self-administration. Of these, we found the expression of miR-199a and 214, which are expressed on the same cluster of chromosome 1, to be upregulated in the female rats exposed to nicotine; upregulation in this group was further validated by real time polymerase chain reaction (RT-PCR). Bioinformatics analysis to assess common targets of miR-199/214 identified Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)- dependent deacetylase that plays a role in apoptosis, neuron survival, and stress resistance. Using western-blot, we confirmed downregulation of SIRT1 and increased cleaved caspase 3 expression in the brains of nicotine-exposed female rats and no change in expression levels in the other groups. Collectively, our findings highlight a miR-199/214 regulatory network that, through SIRT1, may be associated with nicotine seeking in females which may serve as a potential therapeutic target for sex-specific treatment approaches.
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Affiliation(s)
- Steven T Pittenger
- Department of Psychology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
- Yale University School of Medicine, Division of Molecular Psychiatry, New Haven, Connecticut, USA
| | - Victoria L Schaal
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Dalia Moore
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Rahul S Guda
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Sneh Koul
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Sowmya V Yelamanchili
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Rick A Bevins
- Department of Psychology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Gurudutt Pendyala
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
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Fang Y, Qiu J, Jiang ZB, Xu SR, Zhou ZH, He RL. Increased serum levels of miR-214 in patients with PCa with bone metastasis may serve as a potential biomarker by targeting PTEN. Oncol Lett 2018; 17:398-405. [PMID: 30655780 DOI: 10.3892/ol.2018.9522] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) are identified to serve key functions in the progression of various tumors. miR-214 is aberrantly expressed in various types of cancer. In the present study, the function of miR-214 and its feasibility as a potential non-invasive biomarker for patients with prostate cancer (PCa) in a hyperplasia group and a control group were investigated. First, RNA was isolated from the serum of 75 patients with PCa with bone metastasis, 65 patients with PCa with no bone metastasis and 70 healthy controls. The level of miR-214 expression was significantly upregulated in the serum of the bone metastasis group compared with the healthy control and non-bone metastasis groups. Expression levels of alkaline phosphatase (ALP), bone sialoprotein (BSP), collagen type I pyridine crosslinking peptide (ICTP) were also evaluated. The results indicated that serum levels of BSP, ALP and ICTP were increased in the bone metastasis group compared with that in the non-bone metastasis group, hyperplasia group and the control group (P<0.05). The expression level of miR-214 is positively associated with poorly differentiated tumors in patients with PCa with a Gleason score >7 (P<0.05). Western blot analysis demonstrated that phosphatase and tensin homolog (PTEN) was a target gene of miR-214. Additionally, silencing of PTEN significantly increased the invasive ability of PC3 cells even when miR-214 expression was inhibited. In summary, serum miR-214 expression may serve as a potential novel non-invasive biomarker for PCa screening through targeting PTEN.
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Affiliation(s)
- Yi Fang
- Department of Anesthesiology, Changsha Central Hospital, Changsha, Hunan 410000, P.R. China
| | - Jun Qiu
- Oncology Department Two, Mawangdui Hospital of Hunan People's Hospital, Changsha, Hunan 410016, P.R. China
| | - Zong-Bin Jiang
- Department of Pain Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - Sheng-Rong Xu
- Department of Pain Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - Zeng-Hua Zhou
- Department of Pain Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - Rui-Lin He
- Department of Pain Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
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Phatak P, Burrows WM, Chesnick IE, Tulapurkar ME, Rao JN, Turner DJ, Hamburger AW, Wang JY, Donahue JM. MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4. Oncotarget 2018; 9:28391-28407. [PMID: 29983868 PMCID: PMC6033339 DOI: 10.18632/oncotarget.25375] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 04/25/2018] [Indexed: 12/24/2022] Open
Abstract
Although microRNA (miR) 199a-3p functions as a tumor suppressor in multiple malignancies, its expression and role in esophageal cancer have not been studied. Based on our previous observation that miR-199a-3p is markedly downregulated in esophageal cancer cell lines relative to esophageal epithelial cells, we examined the function of miR-199a-3p in these cells. MiR-199a-3p is predicted to bind with high affinity to the mRNA of p21 activated kinase 4 (PAK4). This kinase has been shown to be overexpressed in several malignancies and to modulate proliferation and motility. The current study is designed to determine whether miR-199a-3p regulates the expression of PAK4 in esophageal cancer cells and to understand the functional consequences of this interaction. Herein, we demonstrate reduced expression of miR-199a-3p in human esophageal cancer specimens and cell lines compared to esophageal epithelial cells, with associated increased expression of PAK4. Forced expression of miR-199a-3p decreases expression of PAK4 in esophageal cancer cell lines. Mechanistic studies reveal that miR-199a-3p binds to the 3'UTR of PAK4 mRNA. This interaction results in reduced levels of PAK4 mRNA due to decreased mRNA stability. Downregulation of PAK4 leads to decreased cyclin D1 (CD1) transcription and protein expression, resulting in markedly impaired cellular proliferation. When PAK4 expression is rescued, both CD1 transcription and protein return to baseline levels. Our results show that miR-199a-3p functions as a tumor suppressor in esophageal cancer cells through repression of PAK4. These findings suggest that both miR-199a-3p and PAK4 may be novel therapeutic targets in the treatment of esophageal cancer.
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Affiliation(s)
- Pornima Phatak
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
| | - Whitney M. Burrows
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | | | - Mohan E. Tulapurkar
- Division of Pulmonary and Critical Care, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jaladanki N. Rao
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
| | - Douglas J. Turner
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
| | - Anne W. Hamburger
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jian-Ying Wang
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - James M. Donahue
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
- Department of Surgery, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA
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Liu J, Liu B, Guo Y, Chen Z, Sun W, Gao W, Wu H, Wang Y. MiR-199a-3p acts as a tumor suppressor in clear cell renal cell carcinoma. Pathol Res Pract 2018; 214:806-813. [PMID: 29773428 DOI: 10.1016/j.prp.2018.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/27/2018] [Accepted: 05/05/2018] [Indexed: 10/16/2022]
Abstract
OBJECTIVES To explore the biological function and mechanism of miR-199a-3p in clear cell renal cell carcinoma (CCRCC). METHODS We investigated the expression of miR-199a-3p in CCRCC through quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Over expression of miR-199a-3p was performed in CCRCC cell lines, and cell growth curve, colony formation capacity, cell invasion, wound healing and cell apoptosis assay were used for investigating the roles of miR-199a-3p in CCRCC. RESULTS The expression of miR-199a-3p in CCRCC tissues was significantly lower than that in para-carcinoma tissues. Functional assay showed that over expression of miR-199a-3p influenced cell growth, colony formation, cell invasion, cell migration and cell apoptosis in CCRCC cell lines. CONCLUSIONS Our work suggested that miR-199a-3p was related to cell growth, colony formation, cell invasion, cell migration and cell apoptosis, which might act as a tumor suppressor in CCRCC.
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Affiliation(s)
- Jianmin Liu
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China.
| | - Beibei Liu
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
| | - Yuanyuan Guo
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
| | - Zhijun Chen
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
| | - Wei Sun
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
| | - Wuyue Gao
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
| | - Hongliang Wu
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
| | - Yan Wang
- Department of Urology, First Affiliated Hospital of Bengbu Medical College, Anhui Province, PR China
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50
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Yang F, Zhao WJ, Jia CL, Li XK, Wang Q, Chen ZL, Jiang DQ. MicroRNA-876-3p functions as a tumor suppressor gene and correlates with cell metastasis in pancreatic adenocarcinoma via targeting JAG2. Am J Cancer Res 2018; 8:636-649. [PMID: 29736309 PMCID: PMC5934554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 02/20/2018] [Indexed: 06/08/2023] Open
Abstract
Dysregulation of microRNA (miRNA) expression in multiple cancers and their vital roles in malignant cancer progression are well investigated. The purpose of this study was to explore the biological roles of miR-876-3p in pancreatic cancer. We used genome-wide gene expression analysis in clinical pancreatic adenocarcinoma samples to identify miR-876-3p down-regulated in pancreatic cancer. We then collected 22 pairs of pancreatic cancer and the corresponding non-cancerous tissues to determine miR-876-3p level, and confirmed that miR-876-3p was significantly down-regulated in pancreatic cancer. Furthermore, functional analysis suggested that overexpression of miR-876-3p suppressed cell growth and aggressively increased cells apoptosis in BXPC-3 and PANC-1 cells, whereas down-regulation led to the opposite results. We identified Jagged2 (JAG2) as a direct target of miR-876-3p, and an inverse correlation between miR-876-3p and JAG2 was observed in pancreatic adenocarcinoma. Moreover, miR-876-3p and a JAG2 siRNA were co-transfected into both PANC-1 and BXPC-3 cells to explore the mechanism of miR-876-3p and JAG2 on pancreatic adenocarcinoma tumorigenesis. Down-regulation of JAG2 inhibited the overexpression effects of miR-876-3p, and up-regulation of JAG2 reversed the effects of overexpressed miR-876-3p. Cumulatively, these results revealed a significant role of the miR-876-3p/JAG2 axis in suppressing pancreatic adenocarcinoma cell growth and aggressiveness.
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Affiliation(s)
- Fu Yang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical UniversityKunming, Yunnan, China
| | - Wan Jun Zhao
- The Department of Thyroid Surgery, West China Hospital, Sichuan UniversityChengdu, Sichuan, China
| | - Cong Li Jia
- Huize Ren An Hospital, Department of General SurgeryQujing, Yunnan, China
| | - Xiao Kai Li
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical UniversityKunming, Yunnan, China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical UniversityKunming, Yunnan, China
| | - Zi Li Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - De Quan Jiang
- The Second Department of General Surgery of Jiangjin Center HospitalChongqing, China
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