|
1
|
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.
Collapse
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.
| |
Collapse
|
|
2
|
Majeed NS, Mohammed MH, Hatem ZA, El-Sehrawy AAMA, Ganesan S, Singh A, Akoul MA, Sudan P, Singh R, Hamad HA. Interplay between NETosis and the lncRNA-microRNA regulatory axis in the immunopathogenesis of cancer. J Physiol Biochem 2025:10.1007/s13105-025-01082-x. [PMID: 40358898 DOI: 10.1007/s13105-025-01082-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 04/14/2025] [Indexed: 05/15/2025]
Abstract
Neutrophil extracellular traps (NETs), web-like complex structures secreted by neutrophils, have emerged as key players in the modulation of immune responses and the immunopathogenesis of immune disorders. Initially described for their antimicrobial function, NETs now play a part in the fundamental processes of cancer biology, including cancer initiation, metastatic dissemination, and immune evasion strategies. NETs hijack anti-tumor immunity by entrapping circulating cancer cells, fostering the growth of tumors, and reorganizing the tumor microenvironment such that it is pro-malignancy. Emerging evidence emphasizes the role of NETosis coupled with non-coding RNAs-long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)-as key regulators of gene expression and controllers of processes vital for cancer growth, such as immune response and programmed cell death processes like apoptosis, necroptosis, pyroptosis, and ferroptosis. Aberrantly expressed non-coding RNAs have been attributed to immune dysregulation and excessive NET production, promoting tumor growth. NETs are also associated with a myriad of pathological conditions, such as autoimmune disorders, cystic fibrosis, sepsis, and thrombotic disorders. New therapeutic approaches-such as DNase therapy and PAD4 inhibitors-target NET production and their degradation to modify immune function and the efficiency of immunotherapies. Further clarification of the intricate interactions of NETosis, lncRNAs, and miRNAs has the potential to establish new strategies for the suppression of the growth of tumors and preventing immune evasion. This review seeks to elucidate the interactions between NETosis and the regulatory networks involving non-coding RNAs that significantly contribute to the immunopathogenesis of cancer.
Collapse
Affiliation(s)
| | - Mohammed Hashim Mohammed
- Medical Laboratory Techniques department, College of Health and medical technology, Al-Maarif University, Anbar, Iraq.
| | - Zainab Amer Hatem
- College of Science, Biotechnology Department, Diyala University, Diyala, Iraq
| | | | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
| | - Marwa Azeez Akoul
- Biotechnology Department, College of Applied Science, Fallujah University, Anbar, Iraq
| | - Puneet Sudan
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Roshni Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Hamad Ali Hamad
- Department of Pathological Analysis, Collage of Applied Sciences, University of Fallujah, Fallujah, Iraq
| |
Collapse
|
|
3
|
Jafari S, Motedayyen H, Javadi P, Jamali K, Moradi Hasan-Abad A, Atapour A, Sarab GA. The roles of lncRNAs and miRNAs in pancreatic cancer: a focus on cancer development and progression and their roles as potential biomarkers. Front Oncol 2024; 14:1355064. [PMID: 38559560 PMCID: PMC10978783 DOI: 10.3389/fonc.2024.1355064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/27/2024] [Indexed: 04/04/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most penetrative malignancies affecting humans, with mounting incidence prevalence worldwide. This cancer is usually not diagnosed in the early stages. There is also no effective therapy against PDAC, and most patients have chemo-resistance. The combination of these factors causes PDAC to have a poor prognosis, and often patients do not live longer than six months. Because of the failure of conventional therapies, the identification of key biomarkers is crucial in the early diagnosis, treatment, and prognosis of pancreatic cancer. 65% of the human genome encodes ncRNAs. There are different types of ncRNAs that are classified based on their sequence lengths and functions. They play a vital role in replication, transcription, translation, and epigenetic regulation. They also participate in some cellular processes, such as proliferation, differentiation, metabolism, and apoptosis. The roles of ncRNAs as tumor suppressors or oncogenes in the growth of tumors in a variety of tissues, including the pancreas, have been demonstrated in several studies. This study discusses the key roles of some lncRNAs and miRNAs in the growth and advancement of pancreatic carcinoma. Because they are involved not only in the premature identification, chemo-resistance and prognostication, also their roles as potential biomarkers for better management of PDAC patients.
Collapse
Affiliation(s)
- Somayeh Jafari
- Department of Molecular Medicine, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Hossein Motedayyen
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Parisa Javadi
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kazem Jamali
- Emergency Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amin Moradi Hasan-Abad
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Atapour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholamreza Anani Sarab
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| |
Collapse
|
|
4
|
Pal A, Ojha A, Ju J. Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer. Int J Mol Sci 2023; 24:17523. [PMID: 38139352 PMCID: PMC10744132 DOI: 10.3390/ijms242417523] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The alarmingly low five-year survival rate for pancreatic cancer presents a global health challenge, contributing to about 7% of all cancer-related deaths. Late-stage diagnosis and high heterogeneity are the biggest hurdles in treating pancreatic cancer. Thus, there is a pressing need to discover novel biomarkers that could help in early detection as well as improve therapeutic strategies. MicroRNAs (miRNAs), a class of short non-coding RNA, have emerged as promising candidates with regard to both diagnostics and therapeutics. Dysregulated miRNAs play pivotal roles in accelerating tumor growth and metastasis, orchestrating tumor microenvironment, and conferring chemoresistance in pancreatic cancer. The differential expression profiles of miRNAs in pancreatic cancer could be utilized to explore novel therapeutic strategies. In this review, we also covered studies on recent advancements in various miRNA-based therapeutics such as restoring miRNAs with a tumor-suppressive function, suppressing miRNA with an oncogenic function, and combination with chemotherapeutic drugs. Despite several challenges in terms of specificity and targeted delivery, miRNA-based therapies hold the potential to revolutionize the treatment of pancreatic cancer by simultaneously targeting multiple signaling pathways.
Collapse
Affiliation(s)
- Amartya Pal
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Anushka Ojha
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- The Northport Veteran’s Administration Medical Center, Northport, NY 11768, USA
| |
Collapse
|
|
5
|
Chakrabortty A, Patton DJ, Smith BF, Agarwal P. miRNAs: Potential as Biomarkers and Therapeutic Targets for Cancer. Genes (Basel) 2023; 14:1375. [PMID: 37510280 PMCID: PMC10378777 DOI: 10.3390/genes14071375] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/25/2023] [Accepted: 06/25/2023] [Indexed: 07/30/2023] Open
Abstract
MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and canine diseases. Most cancers tested to date have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we comprehensively summarized the importance of miRNA in human and canine cancer research. We discussed the current state of development and potential for the miRNA as both a diagnostic marker and a therapeutic target.
Collapse
Affiliation(s)
- Atonu Chakrabortty
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Daniel J Patton
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Bruce F Smith
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Payal Agarwal
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| |
Collapse
|
|
6
|
Almanzar VMD, Shah K, LaComb JF, Mojumdar A, Patel HR, Cheung J, Tang M, Ju J, Bialkowska AB. 5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro. Int J Mol Sci 2023; 24:3954. [PMID: 36835366 PMCID: PMC9961454 DOI: 10.3390/ijms24043954] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCreERTM and Ptf1aCreERTM;LSL-KrasG12D mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGFβ1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFβ1 treatment exerted a more substantial effect than TGFβ1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise.
Collapse
Affiliation(s)
- Vanessa M. Diaz Almanzar
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Kunal Shah
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph F. LaComb
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Aisharja Mojumdar
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Hetvi R. Patel
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Jacky Cheung
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Meiyi Tang
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Agnieszka B. Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| |
Collapse
|
|
7
|
Patel HR, Diaz Almanzar VM, LaComb JF, Ju J, Bialkowska AB. The Role of MicroRNAs in Pancreatitis Development and Progression. Int J Mol Sci 2023; 24:1057. [PMID: 36674571 PMCID: PMC9862468 DOI: 10.3390/ijms24021057] [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: 11/15/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023] Open
Abstract
Pancreatitis (acute and chronic) is an inflammatory disease associated with significant morbidity, including a high rate of hospitalization and mortality. MicroRNAs (miRs) are essential post-transcriptional modulators of gene expression. They are crucial in many diseases' development and progression. Recent studies have demonstrated aberrant miRs expression patterns in pancreatic tissues obtained from patients experiencing acute and chronic pancreatitis compared to tissues from unaffected individuals. Increasing evidence showed that miRs regulate multiple aspects of pancreatic acinar biology, such as autophagy, mitophagy, and migration, impact local and systemic inflammation and, thus, are involved in the disease development and progression. Notably, multiple miRs act on pancreatic acinar cells and regulate the transduction of signals between pancreatic acinar cells, pancreatic stellate cells, and immune cells, and provide a complex interaction network between these cells. Importantly, recent studies from various animal models and patients' data combined with advanced detection techniques support their importance in diagnosing and treating pancreatitis. In this review, we plan to provide an up-to-date summary of the role of miRs in the development and progression of pancreatitis.
Collapse
Affiliation(s)
- Hetvi R. Patel
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Vanessa M. Diaz Almanzar
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph F. LaComb
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Agnieszka B. Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| |
Collapse
|
|
8
|
Crosstalk between miRNAs and signaling pathways involved in pancreatic cancer and pancreatic ductal adenocarcinoma. Eur J Pharmacol 2021; 901:174006. [PMID: 33711308 DOI: 10.1016/j.ejphar.2021.174006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/19/2021] [Accepted: 03/02/2021] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide with 5-year survival rates below 8%. Most patients with PC and pancreatic ductal adenocarcinoma (PDAC) die after relapse and cancer progression as well as resistance to treatment. Pancreatic tumors contain a high desmoplastic stroma that forms a rigid mass and has a potential role in tumor growth and metastasis. PC initiates from intraepithelial neoplasia lesions leading to invasive cancer through various pathways. These lesions harbor particular changes in signaling pathways involved in the tumorigenesis process. These events affect both the epithelial cells, including the tumor and the surrounding stroma, and eventually lead to the formation of complex signaling networks. Genetic studies of PC have revealed common molecular features such as the presence of mutations in KRAS gene in more than 90% of patients, as well as the inactivation or deletion mutations of some tumor suppressor genes including TP53, CDKN2A, and SMAD4. In recent years, studies have also identified different roles of microRNAs in PC pathogenesis as well as their importance in PC diagnosis and treatment, and their involvement in various signaling pathways. In this study, we discussed the most common pathways involved in PC and PDAC as well as their role in tumorigenesis and progression. Furthermore, the miRNAs participating in the regulation of these signaling pathways in PC progression are summarized in this study. Therefore, understanding more about pathways involved in PC can help with the development of new and effective therapies in the future.
Collapse
|
|
9
|
Thorenoor N, Phelps DS, Floros J. Differential Sex-Dependent Regulation of the Alveolar Macrophage miRNome of SP-A2 and co-ex (SP-A1/SP-A2) and Sex Differences Attenuation after 18 h of Ozone Exposure. Antioxidants (Basel) 2020; 9:antiox9121190. [PMID: 33260937 PMCID: PMC7768498 DOI: 10.3390/antiox9121190] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/19/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2, and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. We investigated whether miRNome differences previously observed between AM from SP-A2 and SP-A1/SP-A2 mice are due to continued qualitative differences or a delayed response of mice carrying a single gene. Methods: Human transgenic (hTG) mice, carrying SP-A2 or both SP-A genes, and SP-A-KO mice were exposed to filtered air (FA) or ozone (O3). AM miRNA levels, target gene expression, and pathways determined 18 h after O3 exposure. RESULTS: We found (a) differences in miRNome due to sex, SP-A genotype, and exposure; (b) miRNome of both sexes was largely downregulated by O3, and co-ex had fewer changed (≥2-fold) miRNAs than either group; (c) the number and direction of the expression of genes with significant changes in males and females in co-ex are almost the opposite of those in SP-A2; (d) the same pathways were found in the studied groups; and (e) O3 exposure attenuated sex differences with a higher number of genotype-dependent and genotype-independent miRNAs common in both sexes after O3 exposure. Conclusion: Qualitative differences between SP-A2 and co-ex persist 18 h post-O3, and O3 attenuates sex differences.
Collapse
Affiliation(s)
- Nithyananda Thorenoor
- Center for Host Defense, Inflammation, and Lung Disease (CHILD) Research, Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA; (N.T.); (D.S.P.)
- Department of Biochemistry & Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA
| | - David S. Phelps
- Center for Host Defense, Inflammation, and Lung Disease (CHILD) Research, Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA; (N.T.); (D.S.P.)
| | - Joanna Floros
- Center for Host Defense, Inflammation, and Lung Disease (CHILD) Research, Department of Pediatrics, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA; (N.T.); (D.S.P.)
- Department of Obstetrics & Gynecology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA
- Correspondence:
| |
Collapse
|
|
10
|
Ji T, Feng W, Zhang X, Zang K, Zhu X, Shang F. HDAC inhibitors promote pancreatic stellate cell apoptosis and relieve pancreatic fibrosis by upregulating miR-15/16 in chronic pancreatitis. Hum Cell 2020; 33:1006-1016. [PMID: 32524326 PMCID: PMC7505886 DOI: 10.1007/s13577-020-00387-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 06/04/2020] [Indexed: 12/21/2022]
Abstract
In chronic pancreatitis, PSCs are activated by proinflammatory cytokines to induce pancreatic fibrogenesis. HDAC inhibition protected against the pancreatic fibrosis and the apoptosis of PSCs through induced apoptosis and depressed inflammation. In our study, we found that miR-15 and miR-16 decreased significantly in chronic pancreatitis and HDAC inhibition could recover the levels of these two miRNAs. HDAC regulated the transcription of miR-15 and miR-16, which then modulate the apoptosis and fibrosis of PSCs. And we proved that Bcl-2 and Smad5 were the target genes of miR-15 and miR-16, which illustrated how HDAC inhibition alleviated the apoptosis and fibrogenesis of PSCs in chronic pancreatitis. These results suggested that HDAC inhibition protects against CP by promoting apoptosis and TGF-β/Smads signaling pathways, and indicated that HDAC inhibition is a potential therapy to alleviate CP patients in clinic, and these need to be explored further.
Collapse
Affiliation(s)
- Ting Ji
- Intensive Care Unit, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Beijing West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Weiguang Feng
- Intensive Care Unit, Huai'an No 4 People's Hospital, 128 Yan'an East Road, Qingjiangpu District, Huai'an, 223002, Jiangsu, China
| | - Xiangcheng Zhang
- Intensive Care Unit, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Beijing West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Kui Zang
- Intensive Care Unit, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Beijing West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Xingxing Zhu
- Intensive Care Unit, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Beijing West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China
| | - Futai Shang
- Intensive Care Unit, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Beijing West Road, Huaiyin District, Huai'an, 223300, Jiangsu, China.
| |
Collapse
|
|
11
|
Chen Y, Shan T, Qu H, Chen Y, Wang N, Xia J. Inhibition of miR-16 Ameliorates Inflammatory Bowel Disease by Modulating Bcl-2 in Mouse Models. J Surg Res 2020; 253:185-192. [PMID: 32361613 DOI: 10.1016/j.jss.2020.03.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 02/19/2020] [Accepted: 03/08/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND In recent years, microRNA (miRNA) is considered as a potential therapy target. To study the regulatory mechanism and therapeutic effect of miRNAs on inflammatory bowel disease (IBD), we investigated microRNAs that regulate apoptosis-related protein B cell lymphoma-2 (Bcl-2). We examined the role of miR-16 in IBD and the effect of inhibiting the expression of miR-16 on disease progression. MATERIALS AND METHODS Dextran sulfate sodium was used to induce ulcerative colitis in mice. RNA and protein were extracted from the rectal mucosa of mice. Real-time quantitative polymerase chain reaction and Western blotting were used to detect the expression of miR-16 and Bcl-2. The effects of miR-16 on intestinal mucosal immunity were studied by real-time quantitative polymerase chain reaction, and inflammatory factors such as interleukin-1β, interleukin-6, and tumor necrosis factor-α were detected. The weight changes, disease activity index, length of the rectal colon, and pathological score of the mice were used to evaluate the effect of inhibiting miR-16 on disease progression. Through the establishment of overexpression and low expression cell lines of miR-16, the regulation of miR-16 on Bcl-2 was studied. RESULTS MiR-16 was overexpressed in the IBD model, whereas Bcl-2 had lower expression in the mucosa. Inhibiting expression of miR-16 significantly decreased the expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α. In mice, the weight change, disease activity index, and pathological score decreased in the experimental group, in which miR-16 was inhibited. High expression of miR-16 can inhibit Bcl-2 expression. CONCLUSIONS MiR-16 plays a critical role in IBD via Bcl-2 and is a promising target in IBD therapy.
Collapse
Affiliation(s)
- Ye Chen
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China
| | - Ting Shan
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China
| | - Huiheng Qu
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China
| | - Yigang Chen
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China
| | - Ning Wang
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China
| | - Jiazeng Xia
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China.
| |
Collapse
|
|
12
|
Xu X, Yu H, Sun L, Zheng C, Shan Y, Zhou Z, Wang C, Chen B. Adipose‑derived mesenchymal stem cells ameliorate dibutyltin dichloride‑induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway. Mol Med Rep 2020; 21:1833-1840. [PMID: 32319628 PMCID: PMC7057804 DOI: 10.3892/mmr.2020.10995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 01/17/2020] [Indexed: 12/20/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ASCs) play a positive role in tissue injury repair and regeneration. The aim of this study was to determine whether ASCs could ameliorate chronic pancreatitis (CP) induced by the injection of dibutyltin dichloride (DBTC) and to elucidate its potential mechanisms. Furthermore, this study also explored whether there was a significant difference if the ASCs were injected via the inferior vena cava or the left gastric artery. CP was induced in rats by a single intravenous administration of DBTC, and the accumulation of collagen and apoptotic rates of pancreatic acinar cells were analyzed. According to the results, ASCs markedly reduced DBTC-induced pancreatic damage and collagen deposition in the rat model of CP. Moreover, ASCs significantly decreased pancreatic cell apoptosis by regulating the expression levels of caspase-3, BAX and Bcl-2. These effects were observed regardless of whether the injection was in the inferior vena cava or the left gastric artery. It was also found that the expression levels of phosphorylated PI3K, AKT and mTOR in pancreatic tissues of the DBTC-induced CP model group were significantly increased, while the expression levels of phosphorylated PI3K, AKT and mTOR in the two treatment groups were markedly decreased. ASCs noticeably suppressed the PI3K/AKT/mTOR pathway in the pancreatic tissue of DBTC-induced CP. This study indicated that ASCs protect against pancreatic fibrosis by modulating the PI3K/AKT/mTOR pathway, and have the potential to be a new strategy for the treatment of CP in the future.
Collapse
Affiliation(s)
- Xiangxiang Xu
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Huajun Yu
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Linxiao Sun
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chenlei Zheng
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yunfeng Shan
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhenxu Zhou
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Cheng Wang
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Bicheng Chen
- Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| |
Collapse
|
|
13
|
Thorenoor N, Kawasawa YI, Gandhi CK, Zhang X, Floros J. Differential Impact of Co-expressed SP-A1/SP-A2 Protein on AM miRNome; Sex Differences. Front Immunol 2019; 10:1960. [PMID: 31475015 PMCID: PMC6707024 DOI: 10.3389/fimmu.2019.01960] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 08/02/2019] [Indexed: 12/04/2022] Open
Abstract
In humans there are two surfactant protein A (SP-A) functional genes SFTPA1 and SFTPA2 encoding innate immune molecules, SP-A1 and SP-A2, respectively, with numerous genetic variants each. SP-A interacts and regulates many of the functions of alveolar macrophages (AM). It is shown that SP-A variants differ in their ability to regulate the AM miRNome in response to oxidative stress (OxS). Because humans have both SP-A gene products, we were interested to determine the combined effect of co-expressed SP-A1/SP-A2 (co-ex) in response to ozone (O3) induced OxS on AM miRNome. Human transgenic (hTG) mice, carrying both SP-A1/SP-A2 (6A2/1A0, co-ex) and SP-A- KO were utilized. The hTG and KO mice were exposed to filtered air (FA) or O3 and miRNA levels were measured after AM isolation with or without normalization to KO. We found: (i) The AM miRNome of co-ex males and females in response to OxS to be largely downregulated after normalization to KO, but after Bonferroni multiple comparison analysis only in females the AM miRNome remained significantly different compared to control (FA); (ii) The targets of the significantly changed miRNAs were downregulated in females and upregulated in males; (iii) Several of the validated mRNA targets were involved in pro-inflammatory response, anti-apoptosis, cell cycle, cellular growth and proliferation; (iv) The AM of SP-A2 male, shown, previously to have major effect on the male AM miRNome in response to OxS, shared similarities with the co-ex, namely in pathways involved in the pro-inflammatory response and anti-apoptosis but also exhibited differences with the cell-cycle, growth, and proliferation pathway being involved in co-ex and ROS homeostasis in SP-A2 male. We speculate that the presence of both gene products vs. single gene products differentially impact the AM responses in males and females in response to OxS.
Collapse
Affiliation(s)
- Nithyananda Thorenoor
- Department of Pediatrics, Center for Host Defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Yuka Imamura Kawasawa
- Departments of Pharmacology and Biochemistry and Molecular Biology, Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Chintan K Gandhi
- Department of Pediatrics, Center for Host Defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Xuesheng Zhang
- Department of Pediatrics, Center for Host Defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Joanna Floros
- Department of Pediatrics, Center for Host Defense, Inflammation, and Lung Disease Research, The Pennsylvania State University College of Medicine, Hershey, PA, United States.,Department of Obstetrics and Gynecology, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| |
Collapse
|
|
14
|
Cai L, Qi B, Wu X, Peng S, Zhou G, Wei Y, Xu J, Chen S, Liu S. Circular RNA Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b. J Mol Cell Cardiol 2019; 130:10-22. [PMID: 30876857 DOI: 10.1016/j.yjmcc.2019.03.007] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 02/12/2019] [Accepted: 03/10/2019] [Indexed: 12/24/2022]
Abstract
The apoptotic death of cardiomyocytes critically contributes to cardiac remodeling after myocardial infarction (MI). Circular RNAs (circRNAs) are important regulators for a variety of biological functions. Circ-Ttc3 represents one of the top highest expressed circRNAs in the heart; however, its role in MI remains unknown. Herein, we found that circ-Ttc3 was markedly upregulated in the ischemic myocardium and the cardiomyocytes subjected to hypoxic insult. Forced expression of circ-Ttc3 in cardiomyocytes counteracted hypoxia-induced ATP depletion and apoptotic death, in sharp contrast to circ-Ttc3 knockdown. Accordingly, experiments with AAV9-cTnt-mediated knockdown of cardiac circ-Ttc3 in a rat model of MI recapitulated the in vitro findings, and showed the deterioration of cardiac dysfunction after MI. Furthermore, we identified that circ-Ttc3 sponged an endogenous miR-15b-5p to sequester and inhibit its activity, leading to the increased Arl2 expression. Conversely, knockdown of Arl2 partially abolished the beneficial effects of circ-Ttc3 overexpression on ATP production and apoptosis of cardiomyocytes. Thus, our findings revealed the cardioprotective role of circ-Ttc3 in MI. The miR-15b-Arl2 regulatory cascade underlies the protection against MI-induced cardiomyocyte apoptosis by circ-Ttc3.
Collapse
Affiliation(s)
- Lidong Cai
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China
| | - Baozhen Qi
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200080, China
| | - Xiaoyu Wu
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China
| | - Shi Peng
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China
| | - Genqing Zhou
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China
| | - Yong Wei
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China
| | - Juan Xu
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China
| | - Songwen Chen
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China.
| | - Shaowen Liu
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Hongkou District, Shanghai, China.
| |
Collapse
|
|
15
|
MiR-15b is a key regulator of proliferation and apoptosis of chondrocytes from patients with condylar hyperplasia by targeting IGF1, IGF1R and BCL2. Osteoarthritis Cartilage 2019; 27:336-346. [PMID: 30521861 DOI: 10.1016/j.joca.2018.09.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 09/10/2018] [Accepted: 09/13/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study aimed to explore potential microRNAs (miRNAs), which participate in the pathological process of condylar hyperplasia (CH) through targeting specific proliferation- and apoptosis- related genes of chondrocytes. METHODS Insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R) and B-cell CLL/lymphoma 2 (BCL2) in CH cartilage were detected by real-time polymerase chain reaction (PCR), Western blot, immunohistochemistry and immunofluorescence. MiRanda and TargetScanS algorithms were used to predict certain miRNAs in CH chondrocytes concurrently modulating the above three genes. MiR-15b was screened and identified using real-time PCR. After transfection of miR-15b mimics or inhibitor into CH chondrocytes, expression of the above three genes was detected by real-time PCR and western blot, meanwhile, cell proliferation and apoptosis was examined by CCK8, cell cycle assays, flow cytometry and Hoechst staining. Dual luciferase activity was performed to identify the direct regulation of miR-15b on IGF1, IGF1R and BCL2. RESULTS Expression of IGF1, IGF1R and BCL2 increased in CH cartilage. Seven microRNAs concurrently correlated with IGF1, IGF1R and BCL2. Among them, only miR-15b significantly changed in CH chondrocytes. Overexpression of miR-15b in CH chondrocytes suppressed the expression of IGF1, IGF1R and BCL2, while it increased when miR-15b was knockdown. Furthermore, miR-15b suppressed their expression by directly binding to its 3'-UTR in these cells. Besides, miR-15b hampered chondrocytes proliferation through targeting IGF1 and IGF1R and accelerated chondrocytes apoptosis through targeting BCL2. CONCLUSION Suppressed miR-15b contributed to enhanced proliferation capacity and weakened apoptosis of chondrocytes through augmentation of IGF1, IGF1R and BCL2, thereby resulting in development of CH.
Collapse
|
|
16
|
Zhang X, Jin T, Huang X, Liu X, Liu Z, Jia Y, Hao J. Effects of the tumor suppressor PTEN on biological behaviors of activated pancreatic stellate cells in pancreatic fibrosis. Exp Cell Res 2018; 373:132-144. [PMID: 30321515 DOI: 10.1016/j.yexcr.2018.10.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/04/2018] [Accepted: 10/09/2018] [Indexed: 12/16/2022]
Abstract
Pancreatic stellate cells (PSCs), when activated, are characterized by proliferation and collagen synthesis, and contribute to extracellular matrix deposition in pancreatic fibrosis. Concomitantly, fibrosis is linked with the loss of PTEN (phosphatase and tensin homolog) protein in several organs. This study investigated the association between PTEN protein levels and the activated or apoptotic status of PSCs in a rat model of chronic pancreatitis. In addition, the activation status and biological behaviors of culture-activated PSCs were analyzed after lentiviral transfection with wildtype or mutant (G129E) PTEN for upregulation, or PTEN short hairpin RNA for downregulation, of PTEN. In vivo, PTEN levels gradually decreased during pancreatic fibrosis, which positively correlated with apoptosis of activated PSCs, but negatively with PSC activation. In vitro, activated PSCs with wildtype PTEN showed less proliferation, migration, and collagen synthesis compared with control PSCs, and greater numbers were apoptotic; activated PSCs with mutant PTEN showed similar, but weaker, effects. Furthermore, AKT and FAK/ERK signaling was involved in this process. In summary, activated PSCs during pancreatic fibrosis in vivo have lower levels of PTEN. In vitro, PTEN appears to prevent PSCs from further activation and promotes apoptosis through regulation of the AKT and FAK/ERK pathways.
Collapse
Affiliation(s)
- Xiaoyun Zhang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Tong Jin
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xiaoxi Huang
- Department of Medical Research, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Xinjuan Liu
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zheng Liu
- Department of Medical Research, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yanjun Jia
- Department of Medical Research, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
| |
Collapse
|
|
17
|
Liu T, Yang T, Xu Z, Tan S, Pan T, Wan N, Li S. MicroRNA-193b-3p regulates hepatocyte apoptosis in selenium-deficient broilers by targeting MAML1. J Inorg Biochem 2018; 186:235-245. [DOI: 10.1016/j.jinorgbio.2018.06.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 06/14/2018] [Accepted: 06/24/2018] [Indexed: 02/08/2023]
|
|
18
|
Lim SM, Park SH, Lee JH, Kim SH, Kim JY, Min JK, Lee GM, Kim YG. Differential expression of microRNAs in recombinant Chinese hamster ovary cells treated with sodium butyrate using digital RNA counting. J Biotechnol 2018; 283:37-42. [PMID: 30012463 DOI: 10.1016/j.jbiotec.2018.07.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 04/13/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023]
Abstract
Sodium butyrate (NaBu) is an efficient supplement for increasing recombinant protein production in Chinese hamster ovary (CHO) cell culture. To elucidate the effects of NaBu on miRNA expression profile in recombinant CHO (rCHO) cells, differentially expressed miRNAs in NaBu-treated rCHO cells were assessed by NanoString nCounter analysis. This result showed that eight mature mouse miRNAs (let-7b, let-7d, miR-15b, miR-25, miR-27a, miR-99a, miR-125a-5p, and miR-125b-5p) were differentially expressed. Furthermore, quantitative real-time RT-PCR analysis of eight mature CHO miRNAs, annotated using a miRBase database, confirmed the transcriptomic findings. Among the potential corresponding target mRNAs for the selected mature miRNAs, seven cell growth-related target genes (e2f2, akt2, mtor, bcl-2, bim, p38α, and bmf) and five N-glycosylation-related target genes (neu1, b4galt3, gale, man1b1 and mgat4a) were selected by considering the effectiveness of NaBu on rCHO cell culture. The altered expression patterns of the 12 target mRNAs were inversely correlated with those of the selected mature miRNAs. Altogether, NanoString nCounter analysis may be useful for identifying differentially expressed miRNAs in rCHO cells.
Collapse
Affiliation(s)
- Sung-Min Lim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea; Department of Bioprocess Engineering, KRIBB School of Biotechnology, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, South Korea
| | - Sun-Hye Park
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea; Department of Bioprocess Engineering, KRIBB School of Biotechnology, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, South Korea
| | - Joo-Hyoung Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea; Department of Biological Sciences, KAIST, 335 Gwahak-ro, Yuseong-gu, Daejeon, South Korea
| | - Sun Hong Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea; Department of Life Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
| | - Jee Yon Kim
- Department of Biological Sciences, KAIST, 335 Gwahak-ro, Yuseong-gu, Daejeon, South Korea
| | - Jeong-Ki Min
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea; Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon,South Korea
| | - Gyun Min Lee
- Department of Biological Sciences, KAIST, 335 Gwahak-ro, Yuseong-gu, Daejeon, South Korea
| | - Yeon-Gu Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea; Department of Bioprocess Engineering, KRIBB School of Biotechnology, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, South Korea.
| |
Collapse
|
|
19
|
Schoepp M, Ströse AJ, Haier J. Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment. Cancers (Basel) 2017; 9:cancers9060054. [PMID: 28538690 PMCID: PMC5483873 DOI: 10.3390/cancers9060054] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/11/2017] [Accepted: 05/12/2017] [Indexed: 12/17/2022] Open
Abstract
The tumor microenvironment, including cancer-associated fibroblasts (CAF), has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell—tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.
Collapse
Affiliation(s)
- Maren Schoepp
- Comprehensive Cancer Center Münster (CCCM), University Hospital Münster, 48149 Münster, Germany.
| | - Anda Jana Ströse
- Nordakademie University of Applied Sciences, Köllner Chaussee 11, 25337 Elmshorn, Germany.
| | - Jörg Haier
- Nordakademie University of Applied Sciences, Köllner Chaussee 11, 25337 Elmshorn, Germany.
| |
Collapse
|
|
20
|
Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol 2017; 23:382-405. [PMID: 28210075 PMCID: PMC5291844 DOI: 10.3748/wjg.v23.i3.382] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.
Collapse
|
|
21
|
Kota J, Hancock J, Kwon J, Korc M. Pancreatic cancer: Stroma and its current and emerging targeted therapies. Cancer Lett 2017; 391:38-49. [PMID: 28093284 DOI: 10.1016/j.canlet.2016.12.035] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies with a 5-year survival rate of 8%. Dense, fibrotic stroma associated with pancreatic tumors is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Targeting stroma is considered as a potential therapeutic strategy to improve anti-cancer drug efficacy and patient survival. Although numerous stromal depletion therapies have reached the clinic, they add little to overall survival and are often associated with toxicity. Furthermore, increasing evidence suggests the anti-tumor properties of stroma. Its complete ablation enhanced tumor progression and reduced survival. Consequently, efforts are now focused on developing stromal-targeted therapies that normalize the reactive stroma and avoid the extremes: stromal abundance vs. complete depletion. In this review, we summarized the state of current and emerging anti-stromal targeted therapies, with major emphasis on the role of miRNAs in PDAC stroma and their potential use as novel therapeutic agents to modulate PDAC tumor-stromal interactions.
Collapse
Affiliation(s)
- Janaiah Kota
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA; The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA; Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
| | - Julie Hancock
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
| | - Jason Kwon
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
| | - Murray Korc
- The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA; Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA; Department of Medicine, IUSM, Indianapolis, IN, USA
| |
Collapse
|
|
22
|
Pothula SP, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Key role of pancreatic stellate cells in pancreatic cancer. Cancer Lett 2016; 381:194-200. [PMID: 26571462 DOI: 10.1016/j.canlet.2015.10.035] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/29/2015] [Accepted: 10/29/2015] [Indexed: 02/07/2023]
Abstract
Pancreatic stellate cells (PSCs) are responsible for producing the collagenous stroma in pancreatic cancer. Findings from the majority of in vitro and in vivo studies to date indicate that PSCs interact with cancer cells as well as with other cellular elements in the stroma including immune cells, endothelial cells and neuronal cells to set up a growth permissive microenvironment for pancreatic tumours. However, two recent studies reporting a protective effect of myofibroblasts in pancreatic cancer have served to remind researchers of the possibility that the role of PSCs in this disease may be context and time-dependent, such that any possible early protective role of PSCs is subverted in later stages by the ability of cancer cells to turn PSCs into cancer-promoting aides. This concept is supported by the development in recent years of several novel therapeutic approaches targeting the stroma that have been successfully applied in pre-clinical settings to inhibit disease progression. A multi-pronged approach aimed at tumour cells as well as stromal elements may be the key to achieving better clinical outcomes in patients with pancreatic cancer.
Collapse
Affiliation(s)
- Srinivasa P Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - David Goldstein
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia
| | - Romano C Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
| |
Collapse
|
|
23
|
Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol 2016; 37:8471-86. [PMID: 27059734 DOI: 10.1007/s13277-016-5035-9] [Citation(s) in RCA: 411] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 03/28/2016] [Indexed: 12/12/2022] Open
Abstract
As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.
Collapse
|
|
24
|
Bucur O. microRNA regulators of apoptosis in cancer. Discoveries (Craiova) 2016; 4:e57. [PMID: 32309578 PMCID: PMC7159826 DOI: 10.15190/d.2016.4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 03/31/2016] [Accepted: 03/31/2016] [Indexed: 12/12/2022] Open
Abstract
This brief review summarizes our current knowledge on the microRNAs that regulate apoptosis machinery and are potentially involved in the dysregulation or deregulation of apoptosis, a well known hallmark of cancer. microRNAs are critical regulators of the most important cellular processes, including apoptosis. Expression of microRNAs is found to be dysregulated in many malignancies, leading to apoptosis inhibition in cancer, or resistance to current therapies. To date, there are over 80 microRNAs directly involved in apoptosis regulation or dysregulation that can impact cancer detection, initiation, progression, invasion, metastasis or resistance to anti-cancer therapy. Development of microRNA-based therapeutic strategies is now taking shape in the clinic. Thus, these microRNAs represent potential targets or tools for cancer therapy in the future.
Collapse
Affiliation(s)
- Octavian Bucur
- Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
| |
Collapse
|
|
25
|
Rainer TH, Leung LY, Chan CPY, Leung YK, Abrigo JM, Wang D, Graham CA. Plasma miR-124-3p and miR-16 concentrations as prognostic markers in acute stroke. Clin Biochem 2016; 49:663-668. [PMID: 26968104 DOI: 10.1016/j.clinbiochem.2016.02.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/19/2016] [Accepted: 02/24/2016] [Indexed: 11/29/2022]
Abstract
OBJECTIVES This study aimed to investigate plasma concentrations of miR-124-3p and miR-16 as prognostic markers in emergency department patients with acute stroke. DESIGN AND METHODS Plasma concentrations of miR-124-3p and miR-16 of 84 stroke patients (presenting to the emergency department within 24h from onset of symptoms) were determined by RT-qPCR. The primary outcome measure was 3-month mortality and the secondary outcome measure was post-stroke modified Rankin Score (mRS). RESULTS Twelve patients (14.3%) died within 3months of hospital admission and forty-one (48.8%) patients as achieved a 3-month mRS>2. Median plasma miR-124-3p concentrations were elevated in patients who died compared to patients who survived (p=0.0052), and its levels were found to be higher in patients with a 3-month mRS>2 compared with patients with mRS≤2 (p=0.0312). Higher plasma miR-16 concentrations were observed in patients who survived than in patients who died (p=0.0394), while its concentrations were lower in patients achieving mRS>2 than in patients with mRS≤2 (p=0.0124). For a subgroup of cases presenting to the emergency department within 6h from time of symptom onset (n=36), plasma miR-124-3p concentrations predicted 3-month mortality with an area under the ROC curve of 0.87 (95%CI: 0.72-0.96). CONCLUSIONS Plasma miR-124-3p and miR-16 are molecular markers which could be useful for the early prediction of mortality and mRS.
Collapse
Affiliation(s)
- Timothy Hudson Rainer
- Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Hong Kong
| | - Ling Yan Leung
- Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Hong Kong
| | - Cangel Pui Yee Chan
- Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Hong Kong
| | - Yuk Ki Leung
- Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Hong Kong
| | - Jill Morales Abrigo
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong
| | - Defeng Wang
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong
| | - Colin A Graham
- Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Hong Kong.
| |
Collapse
|
|
26
|
Trichostatin A induces a unique set of microRNAs including miR-129-5p that blocks cyclin-dependent kinase 6 expression and proliferation in H9c2 cardiac myocytes. Mol Cell Biochem 2016; 415:39-49. [DOI: 10.1007/s11010-016-2675-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 02/17/2016] [Indexed: 01/07/2023]
|
|
27
|
Chijiiwa Y, Moriyama T, Ohuchida K, Nabae T, Ohtsuka T, Miyasaka Y, Fujita H, Maeyama R, Manabe T, Abe A, Mizuuchi Y, Oda Y, Mizumoto K, Nakamura M. Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. Int J Oncol 2016; 48:1688-700. [PMID: 26892887 DOI: 10.3892/ijo.2016.3389] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/21/2016] [Indexed: 11/05/2022] Open
Abstract
Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P=0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.
Collapse
Affiliation(s)
- Yoshiro Chijiiwa
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Taiki Moriyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshinaga Nabae
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takao Ohtsuka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Miyasaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hayato Fujita
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Maeyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuya Manabe
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Abe
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Mizuuchi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
28
|
Aberrant regulation of miR-15b in human malignant tumors and its effects on the hallmarks of cancer. Tumour Biol 2015; 37:177-83. [DOI: 10.1007/s13277-015-4269-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 10/15/2015] [Indexed: 12/22/2022] Open
|
|
29
|
Srinivas C, Ramaiah MJ, Lavanya A, Yerramsetty S, Kavi Kishor PB, Basha SA, Kamal A, Bhadra U, Bhadra MP. Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer. PLoS One 2015; 10:e0142006. [PMID: 26551008 PMCID: PMC4638343 DOI: 10.1371/journal.pone.0142006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/15/2015] [Indexed: 12/19/2022] Open
Abstract
Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.
Collapse
Affiliation(s)
- Chatla Srinivas
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | - M. Janaki Ramaiah
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- School of Chemical and Biotechnology, SASTRA University, Thanjavur, India
| | - A. Lavanya
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | - Suresh Yerramsetty
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | | | - Shaik Anver Basha
- Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | - Ahmed Kamal
- Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
| | - Utpal Bhadra
- Functional Genomics and Gene Silencing Group, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Manika-Pal Bhadra
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- * E-mail:
| |
Collapse
|
|
30
|
Abstract
PURPOSE OF REVIEW Ever since the first descriptions of methods to isolate pancreatic stellate cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these cells and their functions in health and disease. This review updates recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer. RECENT FINDINGS Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer. SUMMARY Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer.
Collapse
Affiliation(s)
- Minote Apte
- Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, and Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | | | | |
Collapse
|
|
31
|
Sun L, Chua CYX, Tian W, Zhang Z, Chiao PJ, Zhang W. MicroRNA Signaling Pathway Network in Pancreatic Ductal Adenocarcinoma. J Genet Genomics 2015; 42:563-577. [PMID: 26554910 DOI: 10.1016/j.jgg.2015.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/16/2015] [Accepted: 07/22/2015] [Indexed: 01/15/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered to be the most lethal and aggressive malignancy with high mortality and poor prognosis. Their responses to current multimodal therapeutic regimens are limited. It is urgently needed to identify the molecular mechanism underlying pancreatic oncogenesis. Twelve core signaling cascades have been established critical in PDAC tumorigenesis by governing a wide variety of cellular processes. MicroRNAs (miRNAs) are aberrantly expressed in different types of tumors and play pivotal roles as post-transcriptional regulators of gene expression. Here, we will describe how miRNAs regulate different signaling pathways that contribute to pancreatic oncogenesis and progression.
Collapse
Affiliation(s)
- Longhao Sun
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Corrine Ying Xuan Chua
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA
| | - Weijun Tian
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhixiang Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Paul J Chiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA
| | - Wei Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
| |
Collapse
|
|
32
|
Santosa D, Castoldi M, Paluschinski M, Sommerfeld A, Häussinger D. Hyperosmotic stress activates the expression of members of the miR-15/107 family and induces downregulation of anti-apoptotic genes in rat liver. Sci Rep 2015. [PMID: 26195352 PMCID: PMC4508667 DOI: 10.1038/srep12292] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
microRNAs are an abundant class of small non-coding RNAs that negatively regulate gene expression. Importantly, microRNA activity has been linked to the control of cellular stress response. In the present study, we investigated whether the expression of hepatic microRNAs is affected by changes in ambient osmolarity. It is shown that hyperosmotic exposure of perfused rat liver induces a rapid upregulation of miR-15a, miR-15b and miR-16, which are members of the miR-15/107 microRNAs superfamily. It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs. Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs. It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.
Collapse
Affiliation(s)
- David Santosa
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Martha Paluschinski
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Annika Sommerfeld
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| |
Collapse
|
|
33
|
Qiao Z, Yuan J, Shen J, Wang C, He Z, Hu Y, Zhang M, Xu C. Effect of thalidomide in combination with gemcitabine on human pancreatic carcinoma SW-1990 cell lines in vitro and in vivo. Oncol Lett 2015; 9:2353-2360. [PMID: 26137070 DOI: 10.3892/ol.2015.3064] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 03/02/2015] [Indexed: 01/08/2023] Open
Abstract
Pancreatic cancer is one of the most frequently occurring malignancies worldwide and it is the fourth most common cause of cancer-associated mortality in Western countries. Thalidomide (THD) plays an important role in tumor therapy, as it is able to promote early stage apoptosis and inhibit the process of angiogenesis. The present study evaluated the ability of the combination of THD and gemcitabine (GEM) to inhibit the growth of the pancreatic cancer SW-1990 cell line in vitro and in vivo. Early apoptosis in the SW-1990 cells was detected by the Annexin V/propidium iodide double staining method, the level of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. In addition, the expression of vascular endothelial growth factor in transplanted tumor tissue was measured by RT-PCR, immunohistochemistry and western blot analysis. Cluster of differentiation 34 positivity was considered to indicate the microvessel density. Subsequent to treatment with THD and GEM alone or in combination, it was found that the expression of Bax was upregulated, while the expression of Bcl-2 was downregulated, and the growth of SW-1990 cells and transplanted tumors in nude mice was evidently inhibited. The administration of THD in combination with GEM may demonstrate a potent antitumor effect that increases with increasing dose. The mechanism behind the antitumor effect may be associated with the inhibition of tumor angiogenesis and induction of the apoptosis pathway.
Collapse
Affiliation(s)
- Zhenguo Qiao
- Department of Gastroenterology, Affiliated Wujiang Hospital of Nantong University, Suzhou, Jiangsu 215200, P.R. China
| | - Jigang Yuan
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing, Jiangsu 210008, P.R. China
| | - Jiaqing Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chao Wang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhilong He
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yijia Hu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Muxing Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| |
Collapse
|
|
34
|
Kuśnierz-Cabala B, Nowak E, Sporek M, Kowalik A, Kuźniewski M, Enguita FJ, Stępień E. Serum levels of unique miR-551-5p and endothelial-specific miR-126a-5p allow discrimination of patients in the early phase of acute pancreatitis. Pancreatology 2015; 15:344-51. [PMID: 26094040 DOI: 10.1016/j.pan.2015.05.475] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 04/08/2015] [Accepted: 05/26/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Vascular dysfunction is a severe complication which can cause organ ischemia and damage during acute pancreatitis (AP). Laboratory assessment of AP is based on several routine parameters and does not reflect endothelial dysfunction or organ injury. Recently, small non-protein-coding RNAs (miRNAs) have been introduced to laboratory diagnostics as new biomarkers or predictive parameters. Candidate miRNAs (hsa-miR-16-5p, -103a-3p, -122-5p, -126-5p, -148a-5p, -216a-5p, -375, and -551b-5b) were selected to check their possible clinical application in stratification of patients with different AP severity. METHODS In this observational study, 62 patients with mild (MAP) and 26 with moderate and severe (SAP) acute pancreatitis were included. The control group consisted of 10 age and sex matched subjects. Circulating miRNAs were analyzed in serum using a quantitative real-time PCR method (q-RT-PCR) by means of 3'-locked-nucleic-acid primers. RESULTS In SAP patients, a significant increase in most of the selected miRNAs (miR-126-5p, -148a-3p, -216a-5p and -551b-5p, and miR-375) was observed when compared to control subjects. In MAP patients, three miRNAs were significantly elevated: endothelial-specific miR-216a-5p, -551b-5p, as well as miR-375 that is highly abundant in pancreas. ROC analysis revealed that miR-126-p and miR-551b-5p can predict AP severity (AUC 0.748, sensitivity 60.0%, specificity 87.1%, p < 0.001) and (AUC 0.716; sensitivity 69.2%, specificity 72.6%, p < 0.001). miR-375 was not relevant (AUC 0.458; sensitivity 55.%, specificity 44.4%). CONCLUSIONS A pancreatic miRNA signature can be useful for assessment of pancreatic injury in the acute phase of AP. Endothelial dysfunction during AP is reflected by levels of specific circulating miRNAs and may help in patient stratification.
Collapse
Affiliation(s)
- Beata Kuśnierz-Cabala
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | - Ewelina Nowak
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Mateusz Sporek
- Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland; Surgery Department of the District Hospital in Sucha Beskidzka, Poland
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Marek Kuźniewski
- Department of Nephrology, Jagiellonian University Medical College, Krakow, Poland
| | - Francisco J Enguita
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ewa Stępień
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland; Department of Medical Physics, M. Smoluchowski Institute of Physics, Jagiellonian University, Krakow, Poland.
| |
Collapse
|
|
35
|
Kang W, Tong JHM, Lung RWM, Dong Y, Zhao J, Liang Q, Zhang L, Pan Y, Yang W, Pang JCS, Cheng ASL, Yu J, To KF. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer 2015; 14:52. [PMID: 25743273 PMCID: PMC4342823 DOI: 10.1186/s12943-015-0323-3] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/16/2015] [Indexed: 12/13/2022] Open
Abstract
Background MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. In this study, the role of miR-15a and miR-16-1 in gastric adenocarcinoma (GAC) was investigated. Methods The expression of miR-15a and miR-16-1 in cell lines and primary tumors was examined by miRNA qRT-PCR. Proliferative assays, colony formation, cell invasion and migration, flow cytometry analysis and in vivo study were performed by ectopic expression of miR-15a and miR-16-1. The putative target genes of miR-15a and miR-16-1 were explored by TargetScan and further validated. Results We found that miR-15a and miR-16-1 were down-regulated in GAC cell lines and primary tumor samples compared with normal gastric epithelium. Functional study demonstrated that ectopic expression of miR-15a and miR-16-1 suppressed cell proliferation, monolayer colony formation, invasion and migration, and xenograft formation in vivo. In addition, miR-15a and miR-16-1 induced G0/G1 cell cycle arrest which was further confirmed by Western blot and qRT-PCR of related cell cycle regulators. YAP1 was confirmed to be a functional target of miR-15a and miR-16-1 in GAC. YAP1 re-expression partly abrogated the inhibitory effect of miR-15a and miR-16-1 in GAC cells. In clinical samples, YAP1 protein expression shows negative correlation with miR-15a and miR-16-1 expression. Conclusion In conclusion, targeting YAP1 by tumor suppressor miRNA miR-15a and miR-16-1 plays inhibitory effect and this might have a therapeutic potential in GAC. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0323-3) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
| | - Joanna H M Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Raymond W M Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Yujuan Dong
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Junhong Zhao
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Qiaoyi Liang
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Li Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Yi Pan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Jesse C S Pang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
| | - Alfred S L Cheng
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. .,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. .,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, PR China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
| |
Collapse
|
|
36
|
Chen Y, Fu LL, Wen X, Liu B, Huang J, Wang JH, Wei YQ. Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy. Apoptosis 2015; 19:1177-89. [PMID: 24850099 DOI: 10.1007/s10495-014-0999-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs), small and non-coding endogenous RNAs ∼22 nucleotides (nt) in length, have been known to regulate approximately 30 % of human gene expression at the post-transcriptional and translational levels. Accumulating data have demonstrated that certain miRNAs could exert an oncogenic and/or tumor suppressive function and might play essential roles in the regulation of apoptosis and autophagy in cancer. In this review, we summarize that certain oncogenic and tumor suppressive miRNAs could modulate apoptotic pathways in different types of cancer. Subsequently, we demonstrate that other miRNAs might play regulatory roles in the autophagic pathways of cancer. A limited number of oncogenic/tumor suppressive miRNAs could regulate apoptosis and autophagy, respectively, and cooperatively. Taken together, these findings would provide a new clue to elucidate more apoptotic and/or autophagic mechanisms of miRNAs for designing potential novel therapeutic strategies in cancer.
Collapse
Affiliation(s)
- Y Chen
- State Key Laboratory of Biotherapy, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Apte MV, Pirola RC, Wilson JS. Pancreatic Stellate Cells. STELLATE CELLS IN HEALTH AND DISEASE 2015:271-306. [DOI: 10.1016/b978-0-12-800134-9.00016-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
38
|
Shang C, Guo Y, Hong Y, Liu YH, Xue YX. MiR-21 up-regulation mediates glioblastoma cancer stem cells apoptosis and proliferation by targeting FASLG. Mol Biol Rep 2014; 42:721-7. [PMID: 25394756 DOI: 10.1007/s11033-014-3820-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 11/08/2014] [Indexed: 11/30/2022]
Abstract
To investigate whether miR-21 can affect the apoptosis and proliferation of glioblastoma cancer stem cells (GSCs) from down-regulating FASLG. The expression of miRNA-21 was detected by quantitative real-time PCR in normal brain tissue and glioblastoma samples, and the changes of miRNA-21 expression between GSCs and non-GSCs were also detected. The apoptosis and proliferation ability of miR-21 in GSCs were analyzed by MTT and flow cytometry assay after anti-miR-21 transfection. For the regulation mechanism analysis of miR-21, TargetScan, PicTar and microRNA were selected to predict some potential target genes of miR-21. The predicted gene was identified to be the direct and specific target gene of miR-21 by luciferase activities assay and western blot. RNA interference technology was used to confirm the apoptosis and proliferation effects of miR-21 were directly induced by FASLG. The expression of miR-21 increased significantly in glioblastoma contrast to normal brain tissue, and miR-21 up-regulated in GSCs remarkably. The proliferation of GSCs cell could be inhibited with high-expression of miR-21 and this effect could be restored by miR-21 knocked down. Mechanism analysis revealed that FASLG was a specific and direct target gene of miR-21. The advanced effects of anti-miR-21 on GSCs apoptosis and proliferation were mediated by expression of silenced FASLG. In summary, aberrantly expressed miR-21 regulates GSCs apoptosis and proliferation partly through directly down-regulating FASLG protein expression in GSCs and this might offer a new potential therapeutic stratagem for glioblastoma.
Collapse
Affiliation(s)
- Chao Shang
- Department of Neurobiology, China Medical University, No. 92 Beier Road, Heping District, Shenyang, 110001, People's Republic of China
| | | | | | | | | |
Collapse
|
|
39
|
Systematic expression profiling analysis identifies specific microRNA-gene interactions that may differentiate between active and latent tuberculosis infection. BIOMED RESEARCH INTERNATIONAL 2014; 2014:895179. [PMID: 25276827 PMCID: PMC4167957 DOI: 10.1155/2014/895179] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 07/01/2014] [Indexed: 12/27/2022]
Abstract
Tuberculosis (TB) is the second most common cause of death from infectious diseases. About 90% of those infected are asymptomatic—the so-called latent TB infections (LTBI), with a 10% lifetime chance of progressing to active TB. To further understand the molecular pathogenesis of TB, several molecular studies have attempted to compare the expression profiles between healthy controls and active TB or LTBI patients. However, the results vary due to diverse genetic backgrounds and study designs and the inherent complexity of the disease process. Thus, developing a sensitive and efficient method for the detection of LTBI is both crucial and challenging. For the present study, we performed a systematic analysis of the gene and microRNA profiles of healthy individuals versus those affected with TB or LTBI. Combined with a series of in silico analysis utilizing publicly available microRNA knowledge bases and published literature data, we have uncovered several microRNA-gene interactions that specifically target both the blood and lungs. Some of these molecular interactions are novel and may serve as potential biomarkers of TB and LTBI, facilitating the development for a more sensitive, efficient, and cost-effective diagnostic assay for TB and LTBI for the Taiwanese population.
Collapse
|
|
40
|
Leung LY, Chan CPY, Leung YK, Jiang HL, Abrigo JM, Wang DF, Chung JSH, Rainer TH, Graham CA. Comparison of miR-124-3p and miR-16 for early diagnosis of hemorrhagic and ischemic stroke. Clin Chim Acta 2014; 433:139-44. [DOI: 10.1016/j.cca.2014.03.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 02/21/2014] [Accepted: 03/04/2014] [Indexed: 10/25/2022]
|
|
41
|
Hu Y, Wan R, Yu G, Shen J, Ni J, Yin G, Xing M, Chen C, Fan Y, Xiao W, Xu G, Wang X, Hu G. Imbalance of Wnt/Dkk negative feedback promotes persistent activation of pancreatic stellate cells in chronic pancreatitis. PLoS One 2014; 9:e95145. [PMID: 24747916 PMCID: PMC3991593 DOI: 10.1371/journal.pone.0095145] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 03/24/2014] [Indexed: 01/11/2023] Open
Abstract
The role of persistent activation of pancreatic stellate cells (PSCs) in the fibrosis associated with chronic pancreatitis (CP) is increasingly being recognized. Recent studies have shown that Wnt signaling is involved in the development of fibrosis in multiple organs, however, the role of specific Wnts in pancreatic fibrosis remains unknown. We investigated the role of Wnt signaling during PSC activation in CP and the effect of β-catenin inhibition and Dickkopf-related protein 1 (Dkk1) restoration on the phenotype of PSCs. CP was induced in mice by repetitive caerulein injection and mouse PSCs were isolated and activated in vitro. The expression of Wnts, β-catenin, secreted frizzled-related proteins (sFRPs) and Dkks was analyzed by quantitative RT-PCR and western blotting. The canonical Wnt signaling pathway was examined by immunofluorescence and western blot detection of nuclear β-catenin expression. The effect of recombinant mouse Dkk-1 (rmDkk-1) on cell proliferation and apoptosis was assessed by flow cytometry, immunofluorescence, immunocytochemistry and Cell Counting Kit-8 (CCK-8) analysis. The expression of β-catenin, collagen1α1, TGFβRII, PDGFRβ and α-SMA in PSCs treated with different concentrations of rmDkk-1 or siRNA against β-catenin was determined by quantitative RT-PCR and western blotting. Wnt2 was the only Wnt whose expression was significantly upregulated in response to PSC activation, and Wnt2 and β-catenin protein levels were significantly increased in the pancreas of CP mice, whereas Dkk-1 expression was evidently decreased. Nuclear β-catenin levels were markedly increased in activated PSCs, and rmDkk-1 suppressed the nuclear translocation of β-catenin and the proliferation and extracellular matrix production of PSCs through the downregulation of PDGFRβ and TGFβRII. Upregulation of Dkk-1 expression increased apoptosis in cultured PSCs. These results indicate that Wnt signaling may mediate the profibrotic effect of PSC activation, and Wnt2/Dkk-1 could be potential therapeutic targets for CP.
Collapse
Affiliation(s)
- Yanling Hu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ge Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Shen
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianbo Ni
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guojian Yin
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Miao Xing
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Congying Chen
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuting Fan
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wenqin Xiao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gang Xu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail: (GH); (XW)
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail: (GH); (XW)
| |
Collapse
|
|
42
|
Jacobs LA, Bewicke-Copley F, Poolman MG, Pink RC, Mulcahy LA, Baker I, Beaman EM, Brooks T, Caley DP, Cowling W, Currie JMS, Horsburgh J, Kenehan L, Keyes E, Leite D, Massa D, McDermott-Rouse A, Samuel P, Wood H, Kadhim M, Carter DRF. Meta-analysis using a novel database, miRStress, reveals miRNAs that are frequently associated with the radiation and hypoxia stress-responses. PLoS One 2013; 8:e80844. [PMID: 24244721 PMCID: PMC3828287 DOI: 10.1371/journal.pone.0080844] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 10/12/2013] [Indexed: 01/08/2023] Open
Abstract
Organisms are often exposed to environmental pressures that affect homeostasis, so it is important to understand the biological basis of stress-response. Various biological mechanisms have evolved to help cells cope with potentially cytotoxic changes in their environment. miRNAs are small non-coding RNAs which are able to regulate mRNA stability. It has been suggested that miRNAs may tip the balance between continued cytorepair and induction of apoptosis in response to stress. There is a wealth of data in the literature showing the effect of environmental stress on miRNAs, but it is scattered in a large number of disparate publications. Meta-analyses of this data would produce added insight into the molecular mechanisms of stress-response. To facilitate this we created and manually curated the miRStress database, which describes the changes in miRNA levels following an array of stress types in eukaryotic cells. Here we describe this database and validate the miRStress tool for analysing miRNAs that are regulated by stress. To validate the database we performed a cross-species analysis to identify miRNAs that respond to radiation. The analysis tool confirms miR-21 and miR-34a as frequently deregulated in response to radiation, but also identifies novel candidates as potentially important players in this stress response, including miR-15b, miR-19b, and miR-106a. Similarly, we used the miRStress tool to analyse hypoxia-responsive miRNAs. The most frequently deregulated miRNAs were miR-210 and miR-21, as expected. Several other miRNAs were also found to be associated with hypoxia, including miR-181b, miR-26a/b, miR-106a, miR-213 and miR-192. Therefore the miRStress tool has identified miRNAs with hitherto unknown or under-appreciated roles in the response to specific stress types. The miRStress tool, which can be used to uncover new insight into the biological roles of miRNAs, and also has the potential to unearth potential biomarkers for therapeutic response, is freely available at http://mudshark.brookes.ac.uk/MirStress.
Collapse
Affiliation(s)
- Laura Ann Jacobs
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Findlay Bewicke-Copley
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Mark Graham Poolman
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Ryan Charles Pink
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Laura Ann Mulcahy
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Isabel Baker
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Ellie-May Beaman
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Travis Brooks
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Daniel Paul Caley
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
| | - William Cowling
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | | | - Jessica Horsburgh
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Lottie Kenehan
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Emma Keyes
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Daniel Leite
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Davide Massa
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Adam McDermott-Rouse
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Priya Samuel
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Hannah Wood
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Munira Kadhim
- Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom
| | | |
Collapse
|
|
43
|
Ke Y, Zhao W, Xiong J, Cao R. Downregulation of miR-16 promotes growth and motility by targeting HDGF in non-small cell lung cancer cells. FEBS Lett 2013; 587:3153-7. [PMID: 23954293 DOI: 10.1016/j.febslet.2013.08.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 08/06/2013] [Accepted: 08/06/2013] [Indexed: 12/23/2022]
Abstract
MicroRNAs play important roles in the development and progression of non-small cell lung cancer (NSCLC). miR-16 functions as a tumor-suppressor and is inhibited in several malignancies. Herein, we validated that miR-16 is downregulated in NSCLC tissue samples and cell lines. Ectopic expression of miR-16 significantly inhibited cell proliferation and colony formation. Moreover, miR-16 suppressed cell migration and invasion in NSCLC cells. Hepatoma-derived growth factor (HDGF) was found to be a direct target of miR-16 in NSCLC cell lines. Rescue experiments showed that the suppressive effect of miR-16 on cell proliferation, colony formation, migration, and invasion is partially mediated by inhibiting HDGF expression. This study indicates that miR-16 might be associated with NSCLC progression, and suggests an essential role for miR-16 in NSCLC.
Collapse
Affiliation(s)
- Yang Ke
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | | | | | | |
Collapse
|
|
44
|
Ni J, Hu G, Xiong J, Shen J, Shen J, Yang L, Tang M, Zhao Y, Ying G, Yu G, Hu Y, Xing M, Wan R, Wang X. Involvement of interleukin-17A in pancreatic damage in rat experimental acute necrotizing pancreatitis. Inflammation 2013; 36:53-65. [PMID: 22990529 DOI: 10.1007/s10753-012-9519-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Interleukin (IL)-17A is a proinflammatory cytokine, which has recently attracted much interest due to its pathogenic role in various inflammatory conditions such as ischemia/reperfusion injury, chronic inflammation, and autoimmune diseases, but the role of IL-17A in acute pancreatitis remains unclear. This study aimed to investigate the role of IL-17A in experimental acute necrotizing pancreatitis (ANP). We analyzed the expression of IL-17A during the pathogenesis of ANP in vivo induced by 3 % sodium taurocholate (NaTc), by microarray test, quantitative real-time PCR, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. The effects of IL-17A on pancreatic acinar cells and pancreatic stellate cells (PSCs) were further investigated in vitro using recombinant rat IL-17A (rIL-17A). Expression of IL-17A was significantly increased following experimental acute pancreatitis. In addition, rIL-17A induced rat pancreatic acinar cell necrosis and promoted expression of several target genes, including IL-6, IL-1β, CXCL1, CXCL2, and CXCL5, in acinar cells and PSCs. These findings suggest that IL-17A may be involved in pancreatic damage by regulating the expression of inflammatory cytokines and chemokines during experimental acute pancreatitis.
Collapse
Affiliation(s)
- Jianbo Ni
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, People's Republic of China
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Xu X, Yang X, Xing C, Zhang S, Cao J. miRNA: The nemesis of gastric cancer (Review). Oncol Lett 2013; 6:631-641. [PMID: 24137382 PMCID: PMC3789097 DOI: 10.3892/ol.2013.1428] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 06/13/2013] [Indexed: 12/31/2022] Open
Abstract
microRNAs (miRNAs) are a group of small non-coding RNAs that are ~22 (18 to 25) nucleotides (nt) long and have been associated with a variety of diseases, including cancer. Increasing evidence indicates that miRNAs are essential in the development, diagnosis, treatment and prognosis of a variety of tumors. The utility of miRNAs as biomarkers for diagnosis and of target molecules for the treatment of cancers is increasingly being recognized. With the discovery of circulating miRNAs, a non-invasive approach for the diagnosis and treatment of cancer has been identified. This review summarizes the role of miRNAs in the development of different tumors, as well as a variety of other biological events. Moreover, this review focuses on analyzing the function and mechanism of gastric cancer-related miRNAs and investigates the importance of circulating miRNAs in gastric cancer, as well as their origin. Finally, this review lists a number of the problems that must be solved prior to miRNAs being used as reliable non-invasive tools for the diagnosis, treatment and prognosis of gastric cancer.
Collapse
Affiliation(s)
- Xiaohui Xu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, P.R. China
| | | | | | | | | |
Collapse
|
|
46
|
Current world literature. Curr Opin Organ Transplant 2013; 18:111-30. [PMID: 23299306 DOI: 10.1097/mot.0b013e32835daf68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
47
|
Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 2012; 3:344. [PMID: 22973234 PMCID: PMC3428781 DOI: 10.3389/fphys.2012.00344] [Citation(s) in RCA: 242] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 08/09/2012] [Indexed: 12/12/2022] Open
Abstract
While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as 20 years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas-chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumor growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.
Collapse
Affiliation(s)
- Minoti V. Apte
- Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South WalesSydney, NSW, Australia
| | | | | |
Collapse
|