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Liu S, Chen J, Liu M, Zhang C, Chao X, Yang H, Wang T, Bi H, Ding Y, Wang Z, Muhammad A, Muhammad M, Zhou B. miR-107 suppresses porcine granulosa cell proliferation and estradiol synthesis while promoting apoptosis via targeting PTGS2. Theriogenology 2025; 238:117367. [PMID: 40024100 DOI: 10.1016/j.theriogenology.2025.117367] [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: 11/29/2024] [Revised: 02/06/2025] [Accepted: 02/25/2025] [Indexed: 03/04/2025]
Abstract
The proliferation, steroid metabolism, and apoptosis of porcine ovarian granulosa cells (GCs) are critical for follicular development. MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally and modulate signaling networks involved in various cellular processes. In this study, we identify miR-107, a conserved miRNA, as a key regulator of porcine follicle development through its effects on GCs proliferation, steroid metabolism, and apoptosis. Our findings demonstrate that miR-107 suppresses GCs proliferation and estradiol synthesis while promoting apoptosis. Mechanistically, miR-107 exerts its regulatory effects by targeting Prostaglandin-Endoperoxide Synthase 2 (PTGS2), binding to the 3' untranslated region (3'-UTR) of its mRNA. Overexpression of PTGS2 positively regulates porcine GCs function, significantly enhancing cell proliferation and steroid synthesis, reducing apoptosis, and increasing the protein levels of HSD3B1 and CYP19A1, which are key members of the ovarian steroidogenesis signaling pathway. These findings highlight the role of miR-107 in regulating porcine follicular development and underscore its potential as a molecular marker for influencing follicle growth and reproductive efficiency.
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Affiliation(s)
- Shuhan Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Jiahao Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Mingzheng Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China; The Academy for Cell and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Chunlei Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Xiaohuan Chao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Huan Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Tianshuo Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Hongwei Bi
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Yuan Ding
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Ziming Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Asim Muhammad
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Mubashir Muhammad
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Bo Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
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Corradi C, Gentiluomo M, Adsay V, Sainz J, Camisa PR, Wlodarczyk B, Crippa S, Tavano F, Capurso G, Campa D. Multi-omic markers of intraductal papillary mucinous neoplasms progression into pancreatic cancer. Semin Cancer Biol 2025; 109:25-43. [PMID: 39733817 DOI: 10.1016/j.semcancer.2024.12.005] [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: 10/23/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and common form of pancreatic cancer, it has no specific symptoms, and most of the patients are diagnosed when the disease is already at an advanced stage. Chemotherapy typically has only a modest effect, making surgery the most effective treatment option. However, only a small percentage of patients are amenable to surgery. One viable strategy to reduce PDAC death burden associated with the disease is to focus on precursor lesions and identify markers able to predict who will evolve into PDAC. While most PDACs are believed to be preceded by pancreatic intraepithelial neoplasms (PanINs), 5-10 % arise from Intraductal papillary mucinous neoplasms (IPMNs), which are mass-forming cystic lesions that are very common in the general population. IPMNs offer an invaluable model of pancreatic carcinogenesis for researchers to analyse, as well as a target population for PDAC early detection by clinicians. The evolution of IPMN into cancer is a complex and multistep process, therefore the identification of individual markers will not be the solution. In recent years, multiple omics technologies have been instrumental to identify possible biomarkers of IPMN progression and carcinogenesis. The only foreseeable strategy will be to integrate multi-omics data, alongside clinical and morphological features, into a progression score or signature using either standard epidemiologic tools or artificial intelligence. The aim of this manuscript is to review the current knowledge on genetic biomarkers and to briefly mention also additional omics, such as metabolomics, the exposome, the miRNome and epigenomics of IPMNs.
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Affiliation(s)
| | | | - Volkan Adsay
- Department of Pathology, Koç University School of Medicine and Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Juan Sainz
- Department of Biochemistry and Molecular Biology, University of Granada, Granada, Spain
| | - Paolo Riccardo Camisa
- Division of Pancreatic Surgery and Transplantation, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Barbara Wlodarczyk
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Stefano Crippa
- Division of Pancreatic Surgery and Transplantation, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy
| | - Gabriele Capurso
- Vita-Salute San Raffaele University, Milan, Italy; Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy.
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Ciobanu OA, Herlea V, Milanesi E, Dobre M, Fica S. miRNA profile in pancreatic neuroendocrine tumors: Preliminary results. Sci Prog 2025; 108:368504251326864. [PMID: 40152231 PMCID: PMC11952036 DOI: 10.1177/00368504251326864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
OBJECTIVE Our understanding of the pathophysiology of pancreatic neuroendocrine tumors (PanNETs) remains incomplete, largely due to their historically underestimated incidence and the perception of these tumors as rare and slow-growing cancers. Additionally, conventional reliance on histological examination alone is gradually being supplemented by the exploration and introduction of molecular biomarkers, such as microRNAs (miRNAs). As miRNAs modulate the expression of multiple genes and pathways involved in the tumorigenesis of PanNETs, these biomarkers hold considerable promise for diagnosis and prognosis applications. In this study, we aimed to identify miRNAs as tissue markers associated with the diagnosis of PanNETs. METHODS We conducted a case-control study including: 7 PanNETs and 19 nontumoral pancreatic tissues obtained from Romanian patients. The samples underwent miRNA profiling via quantitative RT-PCR to assess the expression of 84 miRNAs. Our results were compared with those obtained by reanalyzing a public dataset. Furthermore, we structured our miRNA expression data according to their targeted mRNAs and their roles in signaling pathways. RESULTS Fourteen miRNAs (miR-1, miR-133a-3p, miR-210-3p, miR-7-5p, miR-10a-5p, miR-92b-3p, miR-132-3p, miR-221-3p, miR-29b-3p, miR-107, miR-103a-3p, let-7b-5p, miR-148a-3p, and miR-202-3p) were identified as differentially expressed by comparing PanNETs with pancreatic nontumoral tissues, with six miRNAs (miR-7-5p, miR-92b-3p, miR-29b-3p, miR-107, miR-103a-3p, and miR-148a-3p) also found in the public dataset analyzed. Bioinformatic analysis revealed that the 14 identified miRNAs target 17 genes. Reanalyzing two public gene expression datasets, five of these genes have been found differentially expressed in PanNET compared to controls. CONCLUSIONS Our preliminary results, albeit limited by a small sample size, highlighted a specific miRNA expression pattern able to distinguish tumoral from normal pancreatic tissue. The diagnostic performance of these miRNAs, matching with circulating miRNAs and validated in more homogeneous and large cohorts, could represent a starting point for improving the diagnostic accuracy of PanNETs.
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Affiliation(s)
- Oana A Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, Bucharest, Romania
- Department of Endocrinology and Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Vlad Herlea
- Fundeni Clinical Institute, Bucharest, Romania
- Department of Pathological Anatomy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Elena Milanesi
- Victor Babes National Institute of Pathology, Bucharest, Romania
- Department of Cellular, Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Maria Dobre
- Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, Bucharest, Romania
- Department of Endocrinology and Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Puente-Rivera J, De la Rosa Pérez DA, Olvera SIN, Figueroa-Angulo EE, Saucedo JGC, Hernández-León O, Alvarez-Sánchez ME. The Circulating miR-107 as a Potential Biomarker Up-Regulated in Castration-Resistant Prostate Cancer. Noncoding RNA 2024; 10:47. [PMID: 39311384 PMCID: PMC11417898 DOI: 10.3390/ncrna10050047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024] Open
Abstract
Prostate cancer (PCa) is a prevalent malignancy in men globally. Current diagnostic methods like PSA testing have limitations, leading to overdiagnosis and unnecessary treatment. Castration-resistant prostate cancer (CRPC) emerges in some patients receiving androgen deprivation therapy (ADT). This study explores the potential of circulating microRNA-107 (miR-107) in liquid biopsies as a prognosis tool to differentiate CRPC from non-castration-resistant PCa (NCRPC). We designed a case-control study to evaluate circulating miR-107 in serum as a potential prognosis biomarker. We analyzed miR-107 expression in liquid biopsies and found significantly higher levels (p < 0.005) in CRPC patients, compared to NCRPC. Notably, miR-107 expression was statistically higher in the advanced stage (clinical stage IV), compared to stages I-III. Furthermore, CRPC patients exhibited significantly higher miR-107 levels (p < 0.05), compared to NCRPC. These findings suggest that miR-107 holds promise as a non-invasive diagnostic biomarker for identifying potential CRPC patients.
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Affiliation(s)
- Jonathan Puente-Rivera
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), San Lorenzo 290, Col. Del Valle, México City 03100, Mexico; (J.P.-R.); (D.A.D.l.R.P.); (E.E.F.-A.)
- División de Investigación, Hospital Juárez de México, Instituto Politécnico Nacional 5160, Col. Magdalena de las Salinas, México City 07360, Mexico
| | - David Alejandro De la Rosa Pérez
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), San Lorenzo 290, Col. Del Valle, México City 03100, Mexico; (J.P.-R.); (D.A.D.l.R.P.); (E.E.F.-A.)
| | - Stephanie I. Nuñez Olvera
- Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City 04510, Mexico;
| | - Elisa Elvira Figueroa-Angulo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), San Lorenzo 290, Col. Del Valle, México City 03100, Mexico; (J.P.-R.); (D.A.D.l.R.P.); (E.E.F.-A.)
| | - José Gadú Campos Saucedo
- Hospital Central Militar, Dirección General de Sanidad SEDENA, Blvd. Manuel Ávila Camacho S/N, Lomas de Sotelo, México City 11200, Mexico;
| | - Omar Hernández-León
- Servicio de Urología, Hospital Juárez de México, Instituto Politécnico Nacional 5160, Col. Magdalena de las Salinas, México City 07360, Mexico;
| | - María Elizbeth Alvarez-Sánchez
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), San Lorenzo 290, Col. Del Valle, México City 03100, Mexico; (J.P.-R.); (D.A.D.l.R.P.); (E.E.F.-A.)
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Zhuo F, Luo S, He W, Feng Z, Hu Y, Xu J, Wang Z, Xu J. The Role of Signaling Pathways in Pancreatic Cancer Targeted Therapy. Am J Clin Oncol 2023; 46:121-128. [PMID: 36735511 DOI: 10.1097/coc.0000000000000979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Signaling pathways play significant roles in the occurrence, development, and treatment of pancreatic cancer (PC). The main treatment options are surgery, chemotherapy, radiotherapy, arterial infusion chemotherapy in interventional therapy, and immunotherapy. Many studies have shown that signaling pathways perform a function in the occurrence and development of PC, for instance, phosphoinositide 3-kinase (PI3K)/AKT, nuclear factor-κB, Ras, interleukin (IL)-17B/IL-17RB, Wnt, and hepatocyte growth factor/c-MET, which play roles in the proliferation, metastasis, invasion, inhibition of apoptosis, promotion of angiogenesis, and drug resistance of PC. Interaction of signaling pathways has an impact on the biological behavior of PC; for example, activation of the neurotensin/NTSR1 pathway, which can activate mitogen-activated protein kinase, nuclear factor-κB, and other pathways related to PC stem cells, play an important role in PC, and an increase in their number is associated with the Wnt/β-catenin and PI3K pathways. Chemotherapy is the main method for the treatment of PC, but drug resistance limits its use. In addition, abnormal activation of IL-17B/IL-17RB signaling pathway is associated with drug resistance. This article discusses the signaling pathways that play different roles in the occurrence and development of PC, as well as current research on signaling pathways in PC treatment.
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Affiliation(s)
- Fangfang Zhuo
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
| | - Shuang Luo
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
| | - Wei He
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
| | - Zhanhui Feng
- Neurological Department, Affiliated Hospital of Guizhou Medical University
| | - Ya'nan Hu
- Department of Cell Biology, Medical College of Soochow University, Suzhou, China
| | - Jingxia Xu
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University
| | - Zejun Wang
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guizhou Medical University
| | - Jianwei Xu
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
- Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang, China
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Effects of miR-107 on Breast Cancer Cell Growth and Death via Regulation of the PTEN/AKT Signaling Pathway. JOURNAL OF ONCOLOGY 2023; 2023:1244067. [PMID: 36816358 PMCID: PMC9931464 DOI: 10.1155/2023/1244067] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/19/2022] [Accepted: 08/26/2022] [Indexed: 02/10/2023]
Abstract
Objective Investigate the influence of miR-107 on breast cancer cell growth and death through the PTEN/AKT signaling pathway. Method As study subjects, the human breast cancer cell line MCF-7 and the normal breast cell line Hs 578Bst were chosen, and MCF-7 cells were, respectively, transfected with control miRNA and miR-107 inhibitor. CCK-8, flow cytometry, scratch assay, and Transwell assay were used to analyze the proliferation, apoptosis, and invasion, and in order to identify the proteins associated with apoptosis in each of the three categories, we used western blot analysis. Bcl-2, cleaved caspase-3, and cleaved caspase-9 expression, as well as PTEN/AKT signaling pathway-associated protein expression, are correlated. Result The expression of miR-107 in MCF-7 cells was significantly greater than that in Hs 578Bst cells, with a P < 0.05 difference; compared to the blank and miRNA control groups, the miR-107 inhibitor group had a P < 0.05 difference. P < 0.05 showed a decrease in proliferation (42.52) but no difference in proliferation between the blank and miRNA control groups (P > 0.05); the miR-107 inhibitor group had higher apoptosis (38.96) with P < 0.05 than the blank group (4.85) and the miRNA control group (5.89); there was no difference in apoptosis between the blank and miRNA groups (P > 0.05). There was no significant difference between the blank group and the miRNA control group with P > 0.05; compared with the blank group, the miR-107 inhibitor group had a lower expression of Bcl-2 protein (0.18), in addition to the degraded paradigms (0.73) and caspase-9 protein concentrations (0.79), respectively. Conclusion The PTEN/AKT signaling pathway may be regulated by miR-107 to limit breast cancer cell growth and increase apoptosis, which suggests that miR-107 may be exploited as a tumor marker for therapeutic therapy.
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Xiao Y, Peng X, Peng Y, Zhang C, Liu W, Yang W, Dou X, Jiang Y, Wang Y, Yang S, Xiang W, Wu T, Li J. Macrophage-derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment. Clin Transl Med 2022; 12:e1071. [PMID: 36229897 PMCID: PMC9561167 DOI: 10.1002/ctm2.1071] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/14/2022] [Accepted: 09/22/2022] [Indexed: 01/28/2023] Open
Abstract
In mammals, ovarian function is dependent on the primordial follicle pool and the rate of primordial follicle activation determines a female's reproductive lifespan. Ovarian ageing is characterised by chronic low-grade inflammation with accelerated depletion of primordial follicles and deterioration of oocyte quality. Macrophages (Mφs) play critical roles in multiple aspects of ovarian functions; however, it remains unclear whether Mφs modulate the primordial follicle pool and what is their role in ovarian ageing. Here, by using super- or naturally ovulated mouse models, we demonstrated for the first time that ovulation-induced local inflammation acted as the driver for selective activation of surrounding primordial follicles in each estrous cycle. This finding was related to infiltrating Mφs in ovulatory follicles and the dynamic changes of the two polarised Mφs, M1 and M2 Mφs, during the process. Further studies on newborn ovaries cocultured with different subtypes of Mφs demonstrated the stimulatory effect of M1 Mφs on primordial follicles, whereas M2 Mφs maintained follicles in a dormant state. The underlying mechanism was associated with the differential regulation of the Phosphatidylinositol 3-kinase/Mechanistic target of rapamycin (PI3K/mTOR) signaling pathway through secreted extracellular vesicles (EVs) and the containing specific miRNAs miR-107 (M1 Mφs) and miR-99a-5p (M2 Mφs). In aged mice, the intravenous injection of M2-EVs improved ovarian function and ameliorated the inflammatory microenvironment within the ovary. Thus, based on the anti-ageing effects of M2 Mφs in old mice, M2-EVs may represent a new approach to improve inflammation-related infertility in women.
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Affiliation(s)
- Yue Xiao
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina,Women's Hospital School of Medicine Zhejiang UniversityZhejiangHangzhouChina
| | - Xiaoxu Peng
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina,Bayer Healthcare Company LimitedPudongShanghaiChina
| | - Yue Peng
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Chi Zhang
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Wei Liu
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Weijie Yang
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina,Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw HospitalZhejiang University School of Medicine, Key Laboratory of Reproductive Dysfunction Management of Zhejiang ProvinceZhejiangHangzhouChina
| | - Xiaowei Dou
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina,Department of Obstetrics and GynecologyThe Second Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Yuying Jiang
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina,Department of Immunology, Key Laboratory of Immunological Environment and Disease, Gusu School, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global HealthNanjing Medical UniversityNanjingJiangsuChina
| | - Yaxuan Wang
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina
| | - Shuo Yang
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina,Department of Immunology, Key Laboratory of Immunological Environment and Disease, Gusu School, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global HealthNanjing Medical UniversityNanjingJiangsuChina
| | - Wenpei Xiang
- Family Planning Research Institute/Center of Reproductive MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Tinghe Wu
- State Key Laboratory of Translational Medicine and Innovative Drug DevelopmentJiangsu Simcere Pharmaceutical Co., Ltd.NanjingJiangsuChina
| | - Jing Li
- State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsuChina
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Kulkarni A, Gayathrinathan S, Nair S, Basu A, Al-Hilal TA, Roy S. Regulatory Roles of Noncoding RNAs in the Progression of Gastrointestinal Cancers and Health Disparities. Cells 2022; 11:2448. [PMID: 35954293 PMCID: PMC9367924 DOI: 10.3390/cells11152448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 01/17/2023] Open
Abstract
Annually, more than a million individuals are diagnosed with gastrointestinal (GI) cancers worldwide. With the advancements in radio- and chemotherapy and surgery, the survival rates for GI cancer patients have improved in recent years. However, the prognosis for advanced-stage GI cancers remains poor. Site-specific GI cancers share a few common risk factors; however, they are largely distinct in their etiologies and descriptive epidemiologic profiles. A large number of mutations or copy number changes associated with carcinogenesis are commonly found in noncoding DNA regions, which transcribe several noncoding RNAs (ncRNAs) that are implicated to regulate cancer initiation, metastasis, and drug resistance. In this review, we summarize the regulatory functions of ncRNAs in GI cancer development, progression, chemoresistance, and health disparities. We also highlight the potential roles of ncRNAs as therapeutic targets and biomarkers, mainly focusing on their ethnicity-/race-specific prognostic value, and discuss the prospects of genome-wide association studies (GWAS) to investigate the contribution of ncRNAs in GI tumorigenesis.
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Affiliation(s)
- Aditi Kulkarni
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
- Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Sharan Gayathrinathan
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Soumya Nair
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Anamika Basu
- Copper Mountain College, Joshua Tree, CA 92252, USA
- Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Taslim A. Al-Hilal
- Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Sourav Roy
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
- Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
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Zhang L, Li B, Li W, Jiang J, Chen W, Yang H, Pan D. miR-107 Attenuates Sepsis-Induced Myocardial Injury by Targeting PTEN and Activating the PI3K/AKT Signaling Pathway. Cells Tissues Organs 2022; 212:523-534. [PMID: 35717938 DOI: 10.1159/000525476] [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: 02/18/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022] Open
Abstract
Sepsis is a public health problem worldwide. This study investigated the mechanism of miR-107 on sepsis-induced myocardial injury. Sepsis rat models were established by cecal ligation and puncture (CLP), and the cell model was established using lipopolysaccharide (LPS)-induced cardiomyocytes. Cardiac function indexes of rats were measured using echocardiography. Pathological changes in the rat myocardium were observed using histological staining. Expression of miR-107 in the serum of rats and in cardiomyocytes was detected after the treatment with miR-107 mimic and/or pcDNA3.1-PTEN, followed by assessment of cell cycle, proliferation, and apoptosis. Binding sites of miR-107 and PTEN were predicted. PTEN, PI3K, p-PI3K, AKT, and p-AKT levels in LPS-induced cardiomyocytes were measured. miR-107 was significantly downregulated in the serum of CLP rats and LPS-induced cardiomyocytes. miR-107 overexpression remarkably improved cardiac function and histological changes, decreased inflammatory factors, and alleviated the sepsis-induced myocardial injury in rats. In LPS-induced cardiomyocytes, miR-107 overexpression increased cardiomyocyte proliferation, inhibited apoptosis, and enhanced the proportion of cardiomyocytes arrested in S and G2/M phases. miR-107 targeted PTEN. PTEN overexpression partially reversed the inhibition of miR-107 mimic on cardiomyocyte apoptosis. miR-107 overexpression activated the PI3K/AKT pathway by inhibiting PTEN. To conclude, miR-107 activates the PI3K/AKT pathway by inhibiting PTEN, thus attenuating sepsis-induced myocardial injury and LPS-induced cardiomyocyte apoptosis.
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Affiliation(s)
- Lin Zhang
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Bin Li
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Wei Li
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Jingbo Jiang
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Wei Chen
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Huayun Yang
- Department of Cardiology, Guilin People's Hospital, Guilin, China
| | - Diguang Pan
- Department of Cardiology, Guilin People's Hospital, Guilin, China
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10
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Khor ES, Noor SM, Wong PF. MiR-107 inhibits the sprouting of intersegmental vessels of zebrafish embryos. PROTOPLASMA 2022; 259:691-702. [PMID: 34368895 DOI: 10.1007/s00709-021-01695-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 07/29/2021] [Indexed: 06/13/2023]
Abstract
MicroRNAs (miRNAs) play important roles in various biological processes. Our previous study showed that inhibition of MTOR with rapamycin treatment suppressed human endothelial cell tube formation, concomitant with the down-regulation of miR-107. Similarly, inhibition of Ztor by rapamycin also suppressed vascular development in zebrafish embryos. To gain a better understanding of the role of miR-107 and MTOR in vascular development, the present study sought to validate its function by over-expressing miR-107 in zebrafish embryos via microinjection with mimic miR-107 duplexes. Alkaline phosphatase (ALP) staining was used to visualise blood vessels in the zebrafish embryo, and expressions of Pten, Ztor and Rap1 were investigated by immunoblotting. Over-expression of miR-107 in zebrafish embryos inhibited the sprouting of intersegmental vessels (ISVs) with concomitant down-regulation of phosphorylated Rps6 expression, which confirmed the inhibition of Ztor signalling. As expected, pten, which is the target of miR-107, was down-regulated. Interestingly, Rap1, a small GTPase protein that is involved in intersomitic vessels sprouting during angiogenesis, was also down-regulated when miR-107 was over-expressed. Overall, our findings suggest that miR-107 and Ztor-mediated suppression of vascular development in zebrafish embryo involves Rap1.
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Affiliation(s)
- Eng-Soon Khor
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Suzita Mohd Noor
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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11
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Popov A, Mandys V. Senescence-Associated miRNAs and Their Role in Pancreatic Cancer. Pathol Oncol Res 2022; 28:1610156. [PMID: 35570840 PMCID: PMC9098800 DOI: 10.3389/pore.2022.1610156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 04/12/2022] [Indexed: 01/17/2023]
Abstract
Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.
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Affiliation(s)
- Alexey Popov
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czechia
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12
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Gao X, Fan X, Zeng W, Liang J, Guo N, Yang X, Zhao Y. Overexpression of microRNA-107 suppressed proliferation, migration, invasion, and the PI3K/Akt signaling pathway and induced apoptosis by targeting Nin one binding (NOB1) protein in a hypopharyngeal squamous cell carcinoma cell line (FaDu). Bioengineered 2022; 13:7881-7893. [PMID: 35294329 PMCID: PMC9208451 DOI: 10.1080/21655979.2022.2051266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Hypopharyngeal squamous cell carcinoma (HSCC) is one of the most common head and neck cancers, with a worst prognosis owing to its aggressivity. MicroRNA-107 (miR-107) is reported to regulate the progression of various cancers. Nevertheless, its implied function in HSCC remains unclear. This study is aimed to exploring the roles and potential mechanisms of miR-107 in HSCC. We found that miR-107 expression was significantly decreased in HSCC tissues compared with the para-cancer tissues. Moreover, miR-107 overexpression by miR-107 mimics decreased FaDu cell viability, led to cell cycle arrest in G1/S phase, accelerated apoptosis, and reduced cell migration and invasion. MiR-107 possibly resulted in deactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, evidenced by the decrease of phosphorylated (p-) PI3K and p-Akt. Besides, dual-luciferase reporter assay confirmed that miR-107 might bind to the 3’UTR of Nin one binding protein 1 (NOB1), and elevated NOB1 expression in HSCC tissues and a negative correlation between miR-107 and NOB1 were found. Rescue assays demonstrated the significant roles of miR-107 in FaDu cell behavior by modulating NOB1. In addition, the tumorigenic potential of miR-107 in vivo was conducted. It was found that miR-107 overexpression in FaDu cells significantly inhibited tumor growth and led to inactivation of the PI3K/Akt signaling. The above findings revealed that miR-107 could suppress FaDu cell proliferation, migration, invasion and induced apoptosis by targeting NOB1 through the PI3K/Akt pathway, suggesting that miR-107/NOB1 axis may exert a key role in FaDu HSCC development.
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Affiliation(s)
- Xin Gao
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Xinlong Fan
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Wei Zeng
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Jiwang Liang
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Nan Guo
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Xiao Yang
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
| | - Yuejiao Zhao
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People's Republic of China
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13
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Zhu X, Wang X, Gong Y, Deng J. E-cadherin on epithelial-mesenchymal transition in thyroid cancer. Cancer Cell Int 2021; 21:695. [PMID: 34930256 PMCID: PMC8690896 DOI: 10.1186/s12935-021-02344-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/15/2021] [Indexed: 02/08/2023] Open
Abstract
Thyroid carcinoma is a common malignant tumor of endocrine system and head and neck. Recurrence, metastasis and high malignant expression after routine treatment are serious clinical problems, so it is of great significance to explore its mechanism and find action targets. Epithelial-mesenchymal transition (EMT) is associated with tumor malignancy and invasion. One key change in tumour EMT is low expression of E-cadherin. Therefore, this article reviews the expression of E-cadherin in thyroid cancers (TC), discuss the potential mechanisms involved, and outline opportunities to exploit E-cadherin on regulating the occurrence of EMT as a critical factor in cancer therapeutics.
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Affiliation(s)
- Xiaoyu Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| | - Xiaoping Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China.
| | - Yifei Gong
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| | - Junlin Deng
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
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14
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Hu J, Li W, Qiao X, Li W, Xie K, Wang Y, Huang B, Zhao Q, Liu L, Fan X. Characterization of microRNA Profiles in Pasteurella multocida-Infected Rabbits and Identification of miR-29-5p as a Regulator of Antibacterial Immune Response. Front Vet Sci 2021; 8:746638. [PMID: 34869721 PMCID: PMC8635715 DOI: 10.3389/fvets.2021.746638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 10/26/2021] [Indexed: 11/13/2022] Open
Abstract
Pasteurella multocida is the pathogenic agent for a variety of severe diseases in livestock, including rabbits. MicroRNAs (miRNAs) participate in the immune response to the pathogen. Distinct miRNA expression patterns were explored in rabbit lung by small-RNA deep sequencing to assess dysregulated miRNAs during P. multocida infection. Totally, 571 miRNAs were screened, of which, 62 were novel, and 32 exhibited differential expression (DE). Of the 32 known DE-miRNAs, 13 and 15 occurred at 1 day and 3 days post-infection (dpi); and ocu-miR-107-3p and ocu-miR-29b-5p were shared between the two time points. Moreover, 7,345 non-redundant target genes were predicted for the 32 DE-miRNAs. Putative target genes were enriched in diverse GO and KEGG pathways and might be crucial for disease resistance. Interestingly, upregulation of ocu-miR-29-5p suppresses P. multocida propagation and downregulates expression of epithelial membrane protein-2 (EMP2) and T-box 4 (TBX4) genes by binding to their 3' untranslated region in RK13 cells. Thus, ocu-miR-29-5p may indirectly inhibit P. multocida invasion by modulating genes related to the host immune response, such as EMP2 and TBX4.
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Affiliation(s)
- Jiaqing Hu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Wenqiang Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Xibo Qiao
- Shandong New Hexin Technology Co. Ltd., Taian, China
| | - Wenjie Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Kerui Xie
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Yanyan Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Bing Huang
- Shandong Provincial Key Laboratory of Poultry Disease Diagnose and Immune, Institute of Poultry, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Qiaoya Zhao
- Shandong Provincial Key Laboratory of Poultry Disease Diagnose and Immune, Institute of Poultry, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Lei Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Xinzhong Fan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
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15
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MicroRNAs in Pancreatic Cancer and Chemoresistance. Pancreas 2021; 50:1334-1342. [PMID: 35041330 DOI: 10.1097/mpa.0000000000001934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading malignancies affecting human health, largely because of the development of resistance to chemotherapy/radiotherapy. There are many mechanisms that mediate the development of drug resistance, such as the transport of antineoplastic agents into cells, shifts in energy metabolism and environment, antineoplastic agent-induced DNA damage, and genetic mutations. MicroRNAs are short, noncoding RNAs that are 20 to 24 nucleotides in length and serve several biological functions. They bind to the 3'-untranslated regions of target genes and induce target degradation or translational inhibition. MicroRNAs can regulate several target genes and mediate PDAC chemotherapy/radiotherapy resistance. The detection of novel microRNAs would not only reveal the molecular mechanisms of PDAC and resistance to chemotherapy/radiotherapy but also provide new approaches to PDAC therapy. MicroRNAs are thus potential therapeutic targets for PDAC and might be essential in uncovering new mechanisms of the disease.
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16
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Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer. Cancer Metastasis Rev 2021; 40:761-776. [PMID: 34591242 PMCID: PMC8556175 DOI: 10.1007/s10555-021-09995-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell–intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types’ function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.
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17
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Han N, Li H, Wang H. MicroRNA-203 inhibits epithelial-mesenchymal transition, migration, and invasion of renal cell carcinoma cells via the inactivation of the PI3K/AKT signaling pathway by inhibiting CAV1. Cell Adh Migr 2021; 14:227-241. [PMID: 32990143 PMCID: PMC7714454 DOI: 10.1080/19336918.2020.1827665] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The present study aimed to evaluate the underlying mechanism of microRNA-203 (miR-203) in renal cell carcinoma (RCC) involving the PI3K/AKT signaling pathway. The results revealed downregulated miR-203 and upregulated CAV1 in RCC tissues. Upregulated miR-203 and downregulated CAV1 increased E-cadherin expression and cell apoptosis, decreased β-catenin and N-cadherin expression and cell proliferation, migration and invasion, and blocked cell cycle entry. CAV1, a target gene of miR-203, decreased by up-regulated miR-203, and silencing CAV1 led to the inactivation of PI3K/AKT signaling pathway. In conclusion, our findings suggested that miR-203-mediated direct suppression of CAV1 inhibits EMT of RCC cells via inactivation of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Ning Han
- Department of Radiology, China-Japan Union Hospital of Jilin University , Changchun, P. R. China
| | - Hai Li
- Department of Urology Surgery, China-Japan Union Hospital of Jilin University , Changchun, P. R. China
| | - Hui Wang
- Department of Ultrasound, China-Japan Union Hospital of Jilin University , Changchun, P. R. China
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18
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Chen X, Wang L, Yu X, Wang S, Zhang J. Caveolin-1 facilitates cell migration by upregulating nuclear receptor 4A2/retinoid X receptor α-mediated β-galactoside α2,6-sialyltransferase I expression in human hepatocarcinoma cells. Int J Biochem Cell Biol 2021; 137:106027. [PMID: 34157397 DOI: 10.1016/j.biocel.2021.106027] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 12/24/2022]
Abstract
It has been reported that caveolin-1 (Cav-1) acts as a tumor promoter in hepatocellular carcinoma (HCC). Our previous studies showed that Cav-1 promoted mouse hepatocarcinoma cell adhesion to fibronectin by upregulating β-galactoside α2,6-sialyltransferase I (ST6Gal-I) expression. However, the detailed mechanism by which Cav-1 regulates ST6Gal-I is not fully understood. In this study, we found that the expression levels of Cav-1 and ST6Gal-I were increased in HCC tissues and correlated with poor prognosis. Cav-1 upregulated ST6Gal-I expression to promote the migration and invasion of HCC cells by inducing epithelial-to-mesenchymal transition. Importantly, the binding of the transcription factor nuclear receptor 4A2/retinoid X receptor alpha (NR4A2/RXRα) to the -550/-200 region of the ST6GAL1 promoter was critical for Cav-1-induced ST6GAL1 gene expression. Furthermore, Cav-1 expression activated the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, followed by upregulation of NR4A2 expression and phosphorylation of RXRα, which facilitated the complex of NR4A2 and phosphorylated RXRα forming and binding to the ST6GAL1 promoter region to induce its transcription. Finally, in the diethylnitrosamine (DEN)-induced HCC murine model, the expression levels of NR4A2, p-RXRα, ST6Gal-I, and α2,6-linked sialic acid decreased in parallel in Cav-1-/- mice compared with Cav-1+/+ mice, which was consistent with the above in vitro results. These findings provide insight into the mechanism of ST6GAL1 gene transcription mediated by Cav-1, which may lead to the development of novel therapeutic strategies targeting metastasis in HCC.
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Affiliation(s)
- Xixi Chen
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Liping Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Xiao Yu
- Department of Pathology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Jianing Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.
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Lin Z, Li Y, Shao R, Hu Y, Gao H. LncRNA TTN-AS1 acts as a tumor promoter in gallbladder carcinoma by regulating miR-107/HMGA1 axis. World J Surg Oncol 2021; 19:163. [PMID: 34090483 PMCID: PMC8180155 DOI: 10.1186/s12957-021-02279-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Background The incidence of gallbladder carcinoma (GBM) in China has increased in recent years. Here, the functional mechanism of lncRNA TTN-AS1 in GBC was preliminary elucidated. Methods The expression levels of lncRNA TTN-AS1, miR-107, and HMGA1 in tissues and cell lines were assessed by RT-qPCR. Cell proliferation was measured by MTT assays. Cell invasion and migration abilities were evaluated by Transwell assays. The relationship between miR-107 and lncRNA TTN-AS1 or HMGA1 was confirmed by luciferase reporter assay. Results Upregulation of lncRNA TTN-AS1 and downregulation of miR-107 were detected in GBC. Furthermore, the expressions between TTN-AS1 and miR-107 were mutually inhibited in GBC. Functionally, lncRNA TTN-AS1 promoted cell viability and motility in GBC by sponging miR-107. In addition, miR-107 directly targets HMGA1. And HMGA1 can be positively regulated by lncRNA TTN-AS1 in GBC. Furthermore, HMGA1 promoted GBC progression by interacting with lncRNA TTN-AS1/miR-107 axis. Conclusion LncRNA TTN-AS1 acted as a tumor promoter in GBC by sponging miR-107 and upregulating HMGA1.
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Affiliation(s)
- Zhaoxia Lin
- Department of Clinical Laboratory, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Shandong Province, Jinan, 250013, China
| | - Yaosheng Li
- Imaging Department, The People's Hospital of Zhangqiu Area, Shandong Province, Jinan, 250200, China
| | - Rongfeng Shao
- Department of Hepatobiliary Vascular Surgery, Qingdao Central Hospital, Qingdao University, Shandong Province, Qingdao, 266000, China
| | - Yuqing Hu
- Department of Endocrinology, The People's Hospital of Zhangqiu Area, Shandong Province, Jinan, 250200, China
| | - Han Gao
- Department of Pathology, Qingdao Municipal Hospital, No. 5 Donghai Middle Road, Shandong Province, Qingdao, 266071, China.
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Sohrabi E, Rezaie E, Heiat M, Sefidi-Heris Y. An Integrated Data Analysis of mRNA, miRNA and Signaling Pathways in Pancreatic Cancer. Biochem Genet 2021; 59:1326-1358. [PMID: 33813720 DOI: 10.1007/s10528-021-10062-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 03/16/2021] [Indexed: 02/06/2023]
Abstract
Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis results also revealed 109 common mRNAs by microarray and mirDIP 4.1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer.
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Affiliation(s)
- Ehsan Sohrabi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Science, Tehran, Iran
| | - Ehsan Rezaie
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Science, P.O. Box 19395-5487, Tehran, Iran.
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Science, Tehran, Iran
| | - Yousef Sefidi-Heris
- Division of Molecular Cell Biology, Department of Biology, Shiraz University, Shiraz, Iran
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21
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Wang L, Xu B, Sun S, Wang B. Overexpression of long non-coding RNA H19 relieves hypoxia-induced injury by down-regulating microRNA-107 in neural stem cells. Neurosci Lett 2021; 753:135855. [PMID: 33785379 DOI: 10.1016/j.neulet.2021.135855] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Neonatal hypoxia-ischemia (HI) is one of the commonest conditions which seriously influences the development of infants' nervous system and causes series of neurological sequelaes. The aim of the present study was to analyze the potential regulatory mechanism of long non-coding (lnc) RNA H19 under hypoxia conditions. METHODS Neural stem cells (NSCs) were incubated in hypoxic conditions for 8 h to induce hypoxia injury. qRT-PCR was performed to detect H19 or micro (miR)-107 expression. Cell Counting Kit-8 (CCK-8) assay and Annexin V-FITC/PI staining assay were employed to detect the effects of hypoxia on cell viability and apoptosis, respectively. Moreover, NSCs were transfected with H19 overexpressing plasmid or shRNA-H19 and then subjected to hypoxia treatment. The effects of H19/miR-107 on NSC cell biological behaviors were confirmed. Furthermore, the signaling pathways involved in HI were analyzed using western blot. RESULTS Hypoxia treatment restrained cell viability and induced cell apoptosis in NSCs. Overexpression of lncRNA H19 attenuated hypoxia-induced NSCs injury, while knockdown of lncRNA H19 aggravated NSCs injury. Further experiments suggested that miR-107 up-regulation reversed the effects of lncRNA H19 overexpression on NSCs. Moreover, the activation of Wnt/β-catenin and PI3K/AKT pathways triggered by H19 were reversed by miR-107 up-regulation in hypoxia-treated NSCs. CONCLUSION LncRNA H19 overexpression attenuated hypoxia-induced NSCs injury and promoted activation of Wnt/β-catenin and PI3K/AKT pathways through downregulating miR-107.
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Affiliation(s)
- Lei Wang
- Department of Pediatrics, Liaocheng Second People's Hospital, The Second Hospital of Liaocheng Affiliated to Shandong First Medical University, Liaocheng, 252600, Shandong, China
| | - Bin Xu
- Department of Pediatrics, Liaocheng Second People's Hospital, The Second Hospital of Liaocheng Affiliated to Shandong First Medical University, Liaocheng, 252600, Shandong, China
| | - Shuying Sun
- Department of Cardiology, Liaocheng Second People's Hospital, The Second Hospital of Liaocheng Affiliated to Shandong First Medical University, Liaocheng, 252600, Shandong, China
| | - Bin Wang
- Department of Children Rehabilitation, Liaocheng Second People's Hospital, The Second Hospital of Liaocheng Affiliated to Shandong First Medical University, Liaocheng, 252600, Shandong, China.
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22
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MicroRNA-107 inhibits proliferation and invasion of laryngeal squamous cell carcinoma cells by targeting CACNA2D1 in vitro. Anticancer Drugs 2021; 31:260-271. [PMID: 31725046 PMCID: PMC7028296 DOI: 10.1097/cad.0000000000000865] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our previous studies have confirmed that α2δ1 has the potential to function as a cancer stem cell marker, and CACNA2D1 is the coding gene of α2δ1. But it is unclear how microRNAs regulate the expression of the CACNA2D1 gene in laryngeal cancer cells. We detected the expressions of α2δ1 protein, microRNA-107, and CACNA2D1 in 40 pairs of laryngeal cancer tissues and adjacent normal tissues. Laryngeal squamous cell carcinoma cells, TU212 and TU686, were cultured and transfected in the blank control group, the agomiR negative control group, the agomiR-107 group, the antagomiR negative control group, or the antagomiR-107 group, and the dual-luciferase reporter assay was employed to assess the regulatory effect of microRNA-107 on CACNA2D1. Then, the effects of microRNA-107 on the biological function of laryngeal squamous cell carcinoma cells were detected by qRT-PCR, Western blot, MTT, cell migration/invasion assay, and cell colony-formation assay. Our data suggested that the protein level of α2δ1, encoded by CACNA2D1, in laryngeal carcinoma tissues was higher than that in adjacent normal tissues, while the expression of microRNA-107 was significantly decreased in laryngeal carcinoma tissues. The dual-luciferase reporter gene assay confirmed that microRNA-107 bound to the 3′-UTR two positions (202-209, 902-908) of CACNA2D1 mRNA. Moreover, the expression of CACNA2D1 and α2δ1 protein were significantly decreased in TU212 and TU686 cells transfected with microRNA-107 expression vectors (P < 0.05), and proliferation, clone formation, migration, and invasion of these cells were also reduced. Furthermore, after knocking down microRNA-107, exactly opposite results were obtained. Overexpression of microRNA-107 can inhibit the proliferation and invasion of laryngeal carcinoma cells in vitro.
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Chen H, Liang C, Wang X, Liu Y, Yang Z, Shen M, Han C, Ren C. The prognostic value of circRNAs for gastric cancer: A systematic review and meta-analysis. Cancer Med 2020; 9:9096-9106. [PMID: 33108710 PMCID: PMC7724307 DOI: 10.1002/cam4.3497] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/03/2020] [Accepted: 09/05/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer-related deaths worldwide. Novel biomarkers circRNAs can play an important role in the development of gastric cancer as oncogenes or tumor suppressor genes. The purpose of this study was to clarify the relationship between the abnormal expression of multiple circRNAs and their prognostic value in gastric cancer patients through a meta-analysis. We researched articles reporting the relationship between circRNAs and the prognosis of gastric cancer published in PubMed, Cochrane, Embase, Web of Science, Wanfang, CNKI, and VIP databases before 31 December 2019. Thirty-five articles were selected for the meta-analysis, involving 3135 gastric cancer patients. The total HR values (95% CI) of OS and DFS related to highly expressed circRNAs that indicated worse prognosis were 1.83 (1.64-2.03; p < 0.001) and 1.66 (1.33-2.07; p < 0.001), respectively. The total HR (95% CI) of OS and DFS related to highly expressed circRNAs that indicated better prognosis was 0.54 (0.45-0.66; p < 0.001) and 0.58 (0.43-0.78; p < 0.001), respectively. Two panels of five circRNAs predicted a more considerable HR value (circ_0009910, hsa_circ_0000467, hsa_circ_0065149, hsa_circ_0081143, and circDLST; and circSMARCA5, circLMTK2, hsa_circ_0001017, hsa_circ_0061276, and circ-KIAA1244). The results of the meta-analysis were 2.63 (2.08-3.33; p < 0.001) and 0.39 (0.27-0.59; p < 0.001) for OS, respectively. The two panels of dysregulated circRNAs can be considered as more suitable potential prognostic tumor biomarkers in patients with gastric cancer because of their larger HR values.
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Affiliation(s)
- Hui Chen
- Geriatric MedicineNorthern Jiangsu People’s HospitalYangzhouChina
| | - Chengtong Liang
- Department of Laboratory MedicineClinical Medical College of Yangzhou UniversityYangzhouChina
| | - Xuechun Wang
- Department of Laboratory MedicineDalian Medical UniversityDalianChina
| | - Yu Liu
- Department of Laboratory MedicineMedical College of Yangzhou UniversityYangzhouChina
| | - Zhanjun Yang
- School of Chemistry and Chemical EngineeringYangzhou UniversityYangzhouChina
| | - Ming Shen
- School of Chemistry and Chemical EngineeringYangzhou UniversityYangzhouChina
| | - Chongxu Han
- Department of Laboratory MedicineClinical Medical College of Yangzhou UniversityYangzhouChina
| | - Chuanli Ren
- Department of Laboratory MedicineClinical Medical College of Yangzhou UniversityYangzhouChina
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Zhou Z, Xia N. LncRNA DCST1-AS1 Sponges miR-107 to Upregulate CDK6 in Cervical Squamous Cell Carcinoma. Cancer Manag Res 2020; 12:7921-7928. [PMID: 32943926 PMCID: PMC7468448 DOI: 10.2147/cmar.s251582] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/10/2020] [Indexed: 12/19/2022] Open
Abstract
Introduction LncRNAs have been reported to play critical roles in liver cancer, while its role in other cancers remains unclear. The aim of this study was to investigate the role of DCST1-AS1 in cervical squamous cell carcinoma (CSCC). Methods Expression of DCST1-AS1 in CSCC tissues and non-tumor tissues from 68 CSCC patients was determined by RT-qPCR. A 5-year follow-up study was carried out to explore the prognostic value of DCST1-AS1 for CSCC. Overexpression of DCST1-AS1 and miR-107 was achieved in CSCC tissues to explore the interaction between them. The roles of DCST1-AS1, miR-107 and CDK6 in regulating the proliferation and viability of CSCC cells were assessed by cell proliferation and viability assays, respectively. Results We found that DCST1-AS1 was upregulated in CSCC and predicted poor survival. RNA interaction prediction showed potential interaction between DCST1-AS1 and miR-107. However, overexpression experiments revealed no significant interaction between them. Moreover, overexpression of DCST1-AS1 led to upregulate CDK6 and increase cell proliferation rate, while overexpression of miR-107 played an opposite role and attenuate the effects of overexpression of DCST1-AS1. Conclusion DCST1-AS1 may sponge miR-107 to upregulate CDK6 in CSCC.
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Affiliation(s)
- Zhigang Zhou
- Department of Gynecological Oncology, Maternal and Child Health Hospital of Hubei Province, Wuhan City, Hubei Province, People's Republic of China
| | - Na Xia
- Department of Gynecological Oncology, Maternal and Child Health Hospital of Hubei Province, Wuhan City, Hubei Province, People's Republic of China
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Zhang Y, Chen D, Zhang G, Wu X, Zhou L, Lin Y, Ding J, An F, Zhan Q. MicroRNA-23b-3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF-κB signaling pathways. Oncol Lett 2020; 20:160. [PMID: 32934728 PMCID: PMC7471709 DOI: 10.3892/ol.2020.12021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNA (miR)-23b-3p plays an important role in tumor growth, proliferation, invasion and migration in pancreatic cancer (PC). However, the function and mechanistic role of miR-23b-3p in the development of PC remains largely unknown. In the present study, the miR-23b-3p levels in the serum of patients with PC were found to be elevated, and the phosphorylation levels of Janus kinase (JAK)2, PI3K, Akt and NF-κВ were found to be upregulated. In addition, miR-23b-3p was induced in response to interleukin-6 (IL-6), which is known to be involved in the progression of PC. Overexpression of miR-23b-3p, on the other hand, activated the JAK/PI3K and Akt/NF-κB signaling pathways in PC cells, as evidenced by miR-23b-3p-induced upregulation of phosphorylated (p-)JAK2, p-PI3K, p-Akt and p-NF-κВ, as well as the downregulation of PTEN; and these effects were found to be reversible by miR-23b-3p inhibition. Furthermore, miR-23b-3p was found to downregulate PTEN by directly targeting the 3′-untranslated region of PTEN mRNA. Notably, in an in vivo xenograft mouse model, overexpression of miR-23b-3p accelerated PC cell-derived tumor growth, activated the JAK/Akt/NF-κВ signaling pathway and promoted liver metastasis. In contrast, knockdown of miR-23b-3p suppressed tumor growth and metastasis as well as JAK/Akt/NF-κВ signaling activity. In vivo imaging of the mice further confirmed the metastasis promoting role of miR-23b-3p in PC. These results suggested that miR-23b-3p enhances PC cell tumorigenesis and metastasis, at least, partially via the JAK/PI3K and Akt/NF-κB signaling pathways. Therefore, targeting miR-23b-3p or the JAK/PI3K and Akt/NF-κB signalings may be potential therapeutic strategy against PC.
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Affiliation(s)
- Yunan Zhang
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Dayang Chen
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Guoqiang Zhang
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Xiongbo Wu
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Liangyun Zhou
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Yexin Lin
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Junli Ding
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Fangmei An
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
| | - Qiang Zhan
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
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Transcriptomic analysis of the mechanisms of alleviating renal interstitial fibrosis using the traditional Chinese medicine Kangxianling in a rat model. Sci Rep 2020; 10:10682. [PMID: 32606425 PMCID: PMC7327068 DOI: 10.1038/s41598-020-67690-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 06/10/2020] [Indexed: 12/16/2022] Open
Abstract
Renal interstitial fibrosis (RIF) is currently recognized as a crucial mechanism of the pathogenesis of chronic kidney disease (CKD). Kangxianling (KXL, anti-fibrin) is a traditional Chinese medicine that has been proven to significantly reduce the levels of ECM deposition and inhibit renal fibrosis.
To characterize the mechanisms and drug targets of KXL, we established a RIF rat model and treated the rats with KXL and losartan. Histological analyses validated the establishment of the RIF model and the treatment effect of KXL. Multiple levels of transcriptomic datasets were generated using lncRNA, mRNA and microRNA sequencing of kidney tissues. Functional annotations and pathway analyses were performed to unravel the therapeutic mechanisms.
A multi-level transcriptomic regulatory network was built to illustrate the core factors in fibrosis pathogenesis and therapeutic regulation. KXL and losartan significantly reduced the progression of RIF, and a better therapeutic effect was shown with higher concentrations of KXL. According to the cluster analysis results of the RNA-seq data, the normal control (NC) and high concentration of KXL (HK) treatment groups were the closest in terms of differentially expressed genes. The WNT, TGF-β and MAPK pathways were enriched and dominated the pathogenesis and therapy of RIF. miR-15b, miR-21, and miR-6216 were upregulated and miR-107 was downregulated in the fibrosis model. These small RNAs were shown to play critical roles in the regulation of the above fibrosis-related genes and could be inhibited by KXL treatment. Finally, based on the lncRNA datasets, we constructed a mRNA-lncRNA-miRNA coexpression ceRNA network, which identified key regulatory factors in the pathogenesis of kidney fibrosis and therapeutic mechanisms of KXL. Our work revealed the potential mechanism of the Chinese medicine Kangxianling in inhibiting renal interstitial fibrosis and supported the clinical use of KXL in the treatment of kidney fibrosis.
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Gu X, Jiang D, Yang Y, Zhang P, Wan G, Gu W, Shi J, Jiang L, Chen B, Zheng Y, Liu D, Guo S, Lu C. Construction and Comprehensive Analysis of Dysregulated Long Noncoding RNA-Associated Competing Endogenous RNA Network in Moyamoya Disease. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:2018214. [PMID: 32617116 PMCID: PMC7306867 DOI: 10.1155/2020/2018214] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 05/09/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by chronic progressive stenosis or occlusion of the bilateral internal carotid artery (ICA), the anterior cerebral artery (ACA), and the middle cerebral artery (MCA). MMD is secondary to the formation of an abnormal vascular network at the base of the skull. However, the etiology and pathogenesis of MMD remain poorly understood. METHODS A competing endogenous RNA (ceRNA) network was constructed by analyzing sample-matched messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA) expression profiles from MMD patients and control samples. Then, a protein-protein interaction (PPI) network was constructed to identify crucial genes associated with MMD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were employed with the DAVID database to investigate the underlying functions of differentially expressed mRNAs (DEmRNAs) involved in the ceRNA network. CMap was used to identify potential small drug molecules. RESULTS A total of 94 miRNAs, 3649 lncRNAs, and 2294 mRNAs were differentially expressed between MMD patients and control samples. A synergistic ceRNA lncRNA-miRNA-mRNA regulatory network was constructed. Core regulatory miRNAs (miR-107 and miR-423-5p) and key mRNAs (STAT5B, FOSL2, CEBPB, and CXCL16) involved in the ceRNA network were identified. GO and KEGG analyses indicated that the DEmRNAs were involved in the regulation of the immune system and inflammation in MMD. Finally, two potential small molecule drugs, CAY-10415 and indirubin, were identified by CMap as candidate drugs for treating MMD. CONCLUSIONS The present study used bioinformatics analysis of candidate RNAs to identify a series of clearly altered miRNAs, lncRNAs, and mRNAs involved in MMD. Furthermore, a ceRNA lncRNA-miRNA-mRNA regulatory network was constructed, which provides insights into the novel molecular pathogenesis of MMD, thus giving promising clues for clinical therapy.
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Affiliation(s)
- Xuefeng Gu
- Research Department, Shanghai University of Medicine & Health Science Affiliated Zhoupu Hospital, Shanghai, China
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Dongyang Jiang
- Department of Cardiology, Pan-Vascular Medicine Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yue Yang
- Key Laboratory of Cancer Prevention and Treatment of Heilongjiang Province, Mudanjiang Medical University, Mudanjiang, China
- Department of Pathology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Peng Zhang
- School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Guoqing Wan
- Research Department, Shanghai University of Medicine & Health Science Affiliated Zhoupu Hospital, Shanghai, China
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Wangxian Gu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Junfeng Shi
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Liying Jiang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Bing Chen
- Department of Neurosurgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Yanjun Zheng
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Dingsheng Liu
- Department of Oncology and Hematology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China
| | - Sufen Guo
- Key Laboratory of Cancer Prevention and Treatment of Heilongjiang Province, Mudanjiang Medical University, Mudanjiang, China
- Department of Pathology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Changlian Lu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai, China
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Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep 2020; 47:4587-4629. [PMID: 32333246 PMCID: PMC7295848 DOI: 10.1007/s11033-020-05435-1] [Citation(s) in RCA: 373] [Impact Index Per Article: 74.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022]
Abstract
Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.
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Affiliation(s)
- Ningni Jiang
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Qijie Dai
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Xiaorui Su
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Jianjiang Fu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Xuancheng Feng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Juan Peng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
- Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
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Zhao F, Wei C, Cui MY, Xia QQ, Wang SB, Zhang Y. Prognostic value of microRNAs in pancreatic cancer: a meta-analysis. Aging (Albany NY) 2020; 12:9380-9404. [PMID: 32420903 PMCID: PMC7288910 DOI: 10.18632/aging.103214] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognostic impact of microRNA (miRNA) expression levels in pancreatic cancer (PC) has been estimated for years, but the outcomes are controversial and heterogeneous. Therefore, we comprehensively reviewed the evidence collected on miRNA expression in PC to determine this effect. RESULTS PC patients with high miR-21 (HR=2.61, 95%CI=1.68-4.04), miR-451a (HR=2.23, 95%CI=1.23-4.04) or miR-1290 (HR=1.43, 95%CI=1.04-1.95) levels in blood had significantly poorer OS (P<0.05). Furthermore, PC patients with high miR-10b (HR=1.73, 95%CI=1.09-2.76), miR-17-5p (HR=1.91, 95%CI=1.30-2.80), miR-21 (HR=1.90, 95%CI=1.61-2.25), miR-23a (HR=2.18, 95%CI=1.52-3.13), miR-155 (HR=2.22, 95%CI=1.27-3.88), miR-203 (HR=1.65, 95%CI=1.14-2.40), miR-221 (HR=1.72, 95%CI=1.08-2.74), miR-222 levels (HR=1.72, 95%CI=1.02-2.91) or low miR-29c (HR=1.39, 95%CI=1.08-1.79), miR-126 (HR=1.55, 95%CI=1.23-1.95), miR-218 (HR=2.62, 95%CI=1.41-4.88) levels in tissues had significantly shorter OS (P<0.05). CONCLUSIONS In summary, blood miR-21, miR-451a, miR-1290 and tissue miR-10b, miR-17-5p, miR-21, miR-23a, miR-29c, miR-126, miR-155, miR-203, miR-218, miR-221, miR-222 had significant prognostic value. METHODS We searched PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews to recognize eligible studies, and 57 studies comprising 5445 PC patients and 15 miRNAs were included to evaluate the associations between miRNA expression levels and overall survival (OS) up to June 1, 2019. Summary hazard ratios (HR) with 95% confidence intervals (CI) were calculated to assess the effect.
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Affiliation(s)
- Fei Zhao
- , Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chao Wei
- College of Integrated Traditional Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Meng-Ying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qiang-Qiang Xia
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Shuai-Bin Wang
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yue Zhang
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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Yang Z, Pu M, Dong X, Ji F, Priya Veeraraghavan V, Yang H. Piperine loaded zinc oxide nanocomposite inhibits the PI3K/AKT/mTOR signaling pathway via attenuating the development of gastric carcinoma: In vitroandin vivostudies. ARAB J CHEM 2020. [DOI: 10.1016/j.arabjc.2020.03.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Li D, Chai L, Yu X, Song Y, Zhu X, Fan S, Jiang W, Qiao T, Tong J, Liu S, Fan L, Lv Z. The HOTAIRM1/miR-107/TDG axis regulates papillary thyroid cancer cell proliferation and invasion. Cell Death Dis 2020; 11:227. [PMID: 32269214 PMCID: PMC7142115 DOI: 10.1038/s41419-020-2416-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 03/16/2020] [Accepted: 03/17/2020] [Indexed: 01/08/2023]
Abstract
The long noncoding RNA (lncRNA), HOX antisense intergenic RNA myeloid 1 (HOTAIRM1), has been shown to act as a tumor suppressor in various human cancers. However, the overall biological roles and clinical significance of HOTAIRM1 in papillary thyroid cancer (PTC) have not been investigated. In this study, we used quantitative reverse transcription PCR (qRT-PCR) to show that HOTAIRM1 was significantly downregulated in PTC tissues and low HOTAIRM1 expression levels were associated with lymph node metastasis and advanced TNM stage. We performed Cell Counting Kit-8, plate colony-formation, flow cytometric apoptosis, transwell, and scratch wound healing assays. Overexpression of HOTAIRM1 was found to inhibit PTC cell proliferation, invasion, and migration in vitro. Additionally, we identified miR-107 as a target of HOTAIRM1 using online bioinformatics tools. Dual-luciferase reporter gene and RNA immunoprecipitation assays were used to confirm that HOTAIRM1 acted as a competing endogenous RNA of miR-107. Furthermore, enhancement of miR-107 could potentially reverse the effects of HOTAIRM1 overexpression in vitro. Inhibition of miR-107 suppressed PTC cell proliferation, invasion, and migration in vitro. HOTAIRM1 overexpression and miR-107 inhibition impaired tumorigenesis in vivo in mouse xenografts. Bioinformatics prediction and a dual-luciferase reporter gene assay demonstrated the binding between miR-107 and the 3'-untranslated region of TDG. The results of qRT-PCR and western blotting assays suggested that HOTAIRM1 could regulate the expression of TDG in an miR-107-meditated manner. In conclusion, we validated HOTAIRM1 as a novel tumor-suppressor lncRNA in PTC and proposed that the HOTAIRM1/miR-107/TDG axis may serve as a therapeutic target for PTC.
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Affiliation(s)
- Dan Li
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Li Chai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Xiaqing Yu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Yingchun Song
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Xuchao Zhu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Suyun Fan
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Wen Jiang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Tingting Qiao
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Junyu Tong
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Simin Liu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China
| | - Lihong Fan
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China.
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China.
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Beaumier A, Robinson SR, Robinson N, Lopez KE, Meola DM, Barber LG, Bulmer BJ, Calvalido J, Rush JE, Yeri A, Das S, Yang VK. Extracellular vesicular microRNAs as potential biomarker for early detection of doxorubicin-induced cardiotoxicity. J Vet Intern Med 2020; 34:1260-1271. [PMID: 32255536 PMCID: PMC7255649 DOI: 10.1111/jvim.15762] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 03/13/2020] [Indexed: 01/21/2023] Open
Abstract
Background Long‐term use of doxorubicin (DOX) is limited by cumulative dose‐dependent cardiotoxicity. Objectives Identify plasma extracellular vesicle (EV)‐associated microRNAs (miRNAs) as a biomarker for cardiotoxicity in dogs by correlating changes with cardiac troponin I (cTnI) concentrations and, echocardiographic and histologic findings. Animals Prospective study of 9 client‐owned dogs diagnosed with sarcoma and receiving DOX single‐agent chemotherapy (total of 5 DOX treatments). Dogs with clinically relevant metastatic disease, preexisting heart disease, or breeds predisposed to cardiomyopathy were excluded. Methods Serum concentration of cTnI was monitored before each treatment and 1 month after the treatment completion. Echocardiography was performed before treatments 1, 3, 5, and 1 month after completion. The EV‐miRNA was isolated and sequenced before treatments 1 and 3, and 1 month after completion. Results Linear mixed model analysis for repeated measurements was used to evaluate the effect of DOX. The miR‐107 (P = .03) and miR‐146a (P = .02) were significantly downregulated whereas miR‐502 (P = .02) was upregulated. Changes in miR‐502 were significant before administration of the third chemotherapeutic dose. When stratifying miRNA expression for change in left ventricular ejection fraction, upregulation of miR‐181d was noted (P = .01). Serum concentration of cTnI changed significantly but only 1 month after treatment completion, and concentrations correlated with left ventricular ejection fraction and left ventricular internal dimension in diastole. Conclusion and Clinical Significance Downregulation of miR‐502 was detected before significant changes in cTnI concentrations or echocardiographic parameters. Further validation using a larger sample size will be required.
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Affiliation(s)
- Amelie Beaumier
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Sally R Robinson
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Nicholas Robinson
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Katherine E Lopez
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Dawn M Meola
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Lisa G Barber
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Barret J Bulmer
- Tufts Veterinary Emergency Treatment & Specialties, Walpole, Massachusetts, USA
| | - Jerome Calvalido
- Tufts Veterinary Emergency Treatment & Specialties, Walpole, Massachusetts, USA
| | - John E Rush
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Ashish Yeri
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Saumya Das
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Vicky K Yang
- Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
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Pinho JD, Silva GEB, Teixeira Júnior AAL, Belfort MRDC, Macedo JM, da Cunha IW, Quintana LG, Calixto JDRR, Nogueira LR, Coelho RWP, Khayat AS. MIR-107, MIR-223-3P and MIR-21-5P Reveals Potential Biomarkers in Penile Cancer. Asian Pac J Cancer Prev 2020; 21:391-397. [PMID: 32102516 PMCID: PMC7332144 DOI: 10.31557/apjcp.2020.21.2.391] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 01/16/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Inguinal lymph node involvement is the main prognostic factor in patients with penile cancer. However, there is a lack of marker/s for lymph node metastasis. microRNAs have been investigated as potential markers for prognosis of various types of cancer. Taking this into consideration, our main goal was to determine the association of miR-223-3p, miR-107, and miR-21-5p expression with clinicopathological characteristics, as well as presence of lymph node metastasis in patients with penile cancer. METHODS Formalin-fixed paraffin-embedded penile squamous cell carcinoma specimens from 50 patients, at diagnosis and prior to any cancer treatment, were obtained. Tissue samples comprising at least 70% malignant cells and adjacent non-tumor tissues were evaluated by using qRT-PCR for expression level of miR-223-3p, miR-107 and miR-21-5p. Additionally, molecular identification of HPV was performed by PCR, and the expression levels of PTEN were analyzed by immunohistochemistry. RESULTS Penile squamous cell carcinoma primary tumors presented higher expression of miR-223-3p, miR-107, and miR-21-5p when compared to non-tumor adjacent tissues. Upregulation of miR-223-3p was associated lymph node metastasis. Higher expression of miR-107 was associated with worsening of prognosis (as observed by histological grade II and III, tumors bigger than 2.0 cm, stage III and IV, and lower disease-free survival). In addition, higher expression of miR-107 and miR-21-5p was correlated to the absence of PTEN protein expression. CONCLUSIONS Our data demonstrate that higher expression of miR-223-3p, miR-107, and miR-21-5p is correlated with poor prognosis in penile cancer. The upregulation of these microRNAs potentially affect critical cancer pathways and may be important for the prognosis and response to therapy in penile cancer.
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Affiliation(s)
| | | | | | | | | | - Isabela Wernerck da Cunha
- Laboratory Immunofluorescence and Electron Microscopy, University Hospital Universitário Presidente Dutra,
| | | | | | | | | | - André Salim Khayat
- Oncologist, Maranhense Institute of Oncology Aldenora Belo, São Luís, MA, Brazil.
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Rao X, Wan L, Jie Z, Zhu X, Yin J, Cao H. Upregulated miR-27a-3p Indicates a Poor Prognosis in Pancreatic Carcinoma Patients and Promotes the Angiogenesis and Migration by Epigenetic Silencing of GATA6 and Activating VEGFA/VEGFR2 Signaling Pathway. Onco Targets Ther 2019; 12:11241-11254. [PMID: 31908490 PMCID: PMC6927607 DOI: 10.2147/ott.s220621] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 11/16/2019] [Indexed: 01/03/2023] Open
Abstract
Background Abnormal miR-27a-3p expression has been frequently reported in several types of human cancer and contributes to tumor progression. However, the role and potential molecular mechanism of miR-27a-3p in the progression of pancreatic carcinoma have not been clarified. Materials and methods The expression of miR-27a-3p and GATA binding protein 6 (GATA6) in pancreatic carcinoma tissues and cell lines was evaluated by quantitative real-time PCR and Western blotting analysis. The relationship between clinical pathologic features and miR-27a-3p expression was analyzed with Chi-square test. The regulatory mechanism of miR-27a-3p on GATA6 was confirmed by luciferase reporter assay and bioinformatics analysis. The effects of miR-27a-3p by targeting GATA6 on cell angiogenesis and migration were assessed by capillary tube formation and wound healing assays. Results MiR-27a-3p expression was significantly upregulated in pancreatic carcinoma tissues and cell lines. Highly expressed miR-27a-3p was closely related to more lymph node metastasis, present peritoneal metastasis, and poor prognosis in patients with pancreatic carcinoma. MiR-27a-3p promoted migration and angiogenesis of pancreatic carcinoma cells by activating vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR2) expression. A significantly negative correlation between GATA6 mRNA and miR-27a-3 expression was found in pancreatic carcinoma samples. Modulation of miR-27a-3p could alter GATA6 expression in pancreatic carcinoma cells. GATA6 was identified as a functional target gene of miR-27a-3p, and GATA6 knockdown partially reversed the effects of miR-27a-3p siliencing on the migration and angiogenesis of pancreatic carcinoma cells by regulation of VEGFA/VEGFR2 pathway. Conclusion Upregulated miR-27a-3p indicates a poor prognosis in pancreatic carcinoma patients and promotes the angiogenesis and migration by epigenetic silencing of GATA6 and activating VEGFA/VEGFR2 signaling pathway, and indicating miR-27a-3p may be a promising therapeutic target for pancreatic carcinoma treatment.
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Affiliation(s)
- Xuefeng Rao
- Department of General Surgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, People's Republic of China
| | - Lihui Wan
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, People's Republic of China
| | - Zhigang Jie
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Xiaoliang Zhu
- Department of General Surgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, People's Republic of China
| | - Junxiang Yin
- Department of General Surgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, People's Republic of China
| | - Hong Cao
- Department of General Surgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang 330006, People's Republic of China
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Li GC, Xin L, Wang YS, Chen Y. Long Intervening Noncoding 00467 RNA Contributes to Tumorigenesis by Acting as a Competing Endogenous RNA against miR-107 in Cervical Cancer Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2293-2310. [PMID: 31640853 DOI: 10.1016/j.ajpath.2019.07.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 06/21/2019] [Accepted: 07/09/2019] [Indexed: 12/14/2022]
Abstract
The functional roles of individual large intervening noncoding RNAs in carcinogenesis and progression of cervical cancer have been uncovered in previous studies. In this study, we aimed to identify the role of long intervening noncoding 00467 (LINC00467) in epithelial-mesenchymal transition (EMT), invasion and migration of cervical cancer cells by regulating miR-107 and kinesin family member 23 (KIF23). Microarray analyses were used to detect cervical cancer-related differentially expressed genes, followed by determination of LINC00467, miR-107, and KIF23 levels and subcellular location of LINC00467. Cervical cancer cells were treated with a series of siRNA and mimics to measure the regulatory role of LINC00467, miR-107, and KIF23 in EMT, cell invasion, migration and proliferation, and tumorigenic ability in vivo and in vitro. LINC00467 and KIF23 were highly expressed, whereas miR-107 was poorly expressed, in cervical cancer. LINC00467 was found to be primarily located in the cytoplasm and function as a competing endogenous RNA against miR-107 to suppress KIF23. Cell proliferation, migration, invasion, and EMT in vitro were inhibited as a result of lentiviral-mediated LINC00467 knockdown and miR-107 overexpression in cervical cancer. In addition, LINC00467 silencing or miR-107 up-regulation repressed tumorigenic ability in xenograft tumor-bearing nude mice in cervical cancer in vivo. LINC00467 silencing or miR-107 up-regulation may serve as novel potential strategies for the treatment of cervical cancer.
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Affiliation(s)
- Guang-Cai Li
- Department of Obstetrics and Gynecology, Linyi People's Hospital, Linyi, People's Republic of China
| | - Li Xin
- Sense Control Office, Economic and Technological Development Zone, People's Hospital of Linyi, Linyi, People's Republic of China
| | - Yong-Sheng Wang
- Department of Obstetrics and Gynecology, Linyi People's Hospital, Linyi, People's Republic of China
| | - Ying Chen
- Department of Obstetrics and Gynecology, Linyi People's Hospital, Linyi, People's Republic of China.
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Gong Y, Yang Y, Tian S, Chen H. Different Role of Caveolin-1 Gene in the Progression of Gynecological Tumors. Asian Pac J Cancer Prev 2019; 20:3259-3268. [PMID: 31759347 PMCID: PMC7062999 DOI: 10.31557/apjcp.2019.20.11.3259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Indexed: 12/13/2022] Open
Abstract
Caveolin-1 (Cav-1), an integral membrane protein, is a principal component of caveolae and has been reported to play a promoting or inhibiting role in cancer progression. Gynecologic tumor is a group of tumors that affect the tissue and organs of the female reproductive system, especially cervical cancer. Cervical cancer, as one of the most common cancers, severely affects female health in developing countries in particular because of its high morbidity and mortality. This review summarizes some mechanisms of Cav-1 in the development and progression of gynecological tumors. The role of Cav-1 in tumorigenesis, including dysregulation of cell cycle, apoptosis and autophagy, adhesion, invasion, and metastasis, such as the formation of invadopodia and matrix metalloproteinase degradation are presented in detail. In addition, Cav-1 modulates autophagy and the formation of invadopodia and target regulated by miRNAs to affect tumor progress. Taken together, we find that, no matter Cav-1 expression in the tumor or stromal cells , Cav-1 has paradoxical role in different types of gynecological tumors in vivo or in vitro and even in the same tumor from the same organ.
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Affiliation(s)
- Yan Gong
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China
| | - Yuhan Yang
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, P. R. China
| | - Sufang Tian
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China
| | - Honglei Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China
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Liu JZ, Hu YL, Feng Y, Guo YB, Liu YF, Yang JL, Mao QS, Xue WJ. Rafoxanide promotes apoptosis and autophagy of gastric cancer cells by suppressing PI3K /Akt/mTOR pathway. Exp Cell Res 2019; 385:111691. [PMID: 31678170 DOI: 10.1016/j.yexcr.2019.111691] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 10/26/2019] [Accepted: 10/28/2019] [Indexed: 02/06/2023]
Abstract
Rafoxanide is commonly used as anti-helminthic medicine in veterinary medicine, a main compound of salicylanilide. Previous studies have reported that rafoxanide, as an inhibitor of BRAF V600E mutant protein, inhibits the growth of colorectal cancer, multiple myeloma, and skin cancer. However, its therapeutic effect on gastric cancer (GC) and the potential mechanism has not been investigated. Here, we have found that rafoxanide inhibited the proliferation of GC cells in vitro, arrested the cell cycle in the G0/G1 phase, and promoted apoptosis and autophagy in GC cells. Treatment with specific autophagy inhibitor 3-methyladenine drastically inhibited the apoptotic cell death effect by suppressing the switch from autophagy to apoptosis. Mechanistically, we found that rafoxanide inhibited the growth of GC cells in vitro by inhibiting the activity of the PI3K/Akt/mTOR signaling pathway. This process induced autophagy, which essentially resulted in the apoptosis of GC cells. Results from subcutaneous implanted tumor models in nude mice also indicated that rafoxanide inhibited the growth of GC cells in vivo. Taken together, our findings revealed that rafoxanide inhibited the growth of GC cells both in vitro and vivo, indicating a potential drug candidate for the treatment of GC.
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Affiliation(s)
- Jia-Zhou Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China
| | - Yi-Lin Hu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China
| | - Ying Feng
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China
| | - Yi-Bing Guo
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China
| | - Yi-Fei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China
| | - Jun-Ling Yang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China
| | - Qin-Sheng Mao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China.
| | - Wan-Jiang Xue
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, China.
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Wang KW, Dong M. Role of circular RNAs in gastric cancer: Recent advances and prospects. World J Gastrointest Oncol 2019; 11:459-469. [PMID: 31236197 PMCID: PMC6580317 DOI: 10.4251/wjgo.v11.i6.459] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 04/06/2019] [Accepted: 04/19/2019] [Indexed: 02/05/2023] Open
Abstract
Circular RNA (circRNA) is a newly discovered non-coding RNA with special structure, which is widely expressed in eukaryotic organisms and mainly located in the cytoplasm. circRNAs participate in gene regulation by working as miRNA sponges that block the inhibitory effect of miRNA on its target genes. In addition, circRNAs can bind to RNA binding proteins to regulate gene expression. Based on characteristics of stability, expression specificity and participation in gene regulation, circRNAs are expected to be biomarkers for early diagnosis of cancer or potential targets for cancer therapy. With the help of bioinformatics analysis, circRNA microarray analysis and high-throughput sequencing technology, more circRNAs were discovered to participate in the progression of gastric cancer (GC) over the past three years. This article gives an overview of these recent research focusing on the roles of circRNAs in GC and highlights the advances.
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Affiliation(s)
- Ke-Wei Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ming Dong
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Eser Ocak P, Ocak U, Tang J, Zhang JH. The role of caveolin-1 in tumors of the brain - functional and clinical implications. Cell Oncol (Dordr) 2019; 42:423-447. [PMID: 30993541 DOI: 10.1007/s13402-019-00447-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Caveolin-1 (cav-1) is the major structural protein of caveolae, the flask-shaped invaginations of the plasma membrane mainly involved in cell signaling. Today, cav-1 is believed to play a role in a variety of disease processes including cancer, owing to the variations of its expression in association with tumor progression, invasive behavior, metastasis and therapy resistance. Since first detected in the brain, a number of studies has particularly focused on the role of cav-1 in the various steps of brain tumorigenesis. In this review, we discuss the different roles of cav-1 and its contributions to the molecular mechanisms underlying the pathobiology and natural behavior of brain tumors including glial, non-glial and metastatic subtypes. These contributions could be attributed to its co-localization with important players in tumorigenesis within the lipid-enriched domains of the plasma membrane. In that regard, the ability of cav-1 to interact with various cell signaling molecules as well as the impact of caveolae depletion on important pathways acting in brain tumor pathogenesis are noteworthy. We also discuss conversant causes hampering the treatment of malignant glial tumors such as limited transport of chemotherapeutics across the blood tumor barrier and resistance to chemoradiotherapy, by focusing on the molecular fundamentals involving cav-1 participation. CONCLUSIONS Cav-1 has the potential to pivot the molecular basis underlying the pathobiology of brain tumors, particularly the malignant glial subtype. In addition, the regulatory effect of cav-1-dependent and caveola-mediated transcellular transport on the permeability of the blood tumor barrier could be of benefit to overcome the restricted transport across brain barriers when applying chemotherapeutics. The association of cav-1 with tumors of the brain other than malignant gliomas deserves to be underlined, as well given the evidence suggesting its potential in predicting tumor grade and recurrence rates together with determining patient prognosis in oligodendrogliomas, ependymomas, meningiomas, vestibular schwannomas and brain metastases.
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Affiliation(s)
- Pinar Eser Ocak
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Umut Ocak
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - John H Zhang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA. .,Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA.
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40
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Tang Z, Fang Y, Du R. MicroRNA-107 induces cell cycle arrests by directly targeting cyclin E1 in ovarian cancer. Biochem Biophys Res Commun 2019; 512:331-337. [DOI: 10.1016/j.bbrc.2019.03.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/02/2019] [Indexed: 12/23/2022]
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Yan Y, Xu Z, Qian L, Zeng S, Zhou Y, Chen X, Wei J, Gong Z. Identification of CAV1 and DCN as potential predictive biomarkers for lung adenocarcinoma. Am J Physiol Lung Cell Mol Physiol 2019; 316:L630-L643. [PMID: 30604627 DOI: 10.1152/ajplung.00364.2018] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is the most common histological form of lung cancer that is clinically diagnosed. The aim of this study is to explore the novel genes associated with LUAD tumorigenesis. Comprehensive bioinformatics analyses of the data were obtained from several publicly available databases, such as the Gene Expression Omnibus, the Human Protein Atlas project, and the Cancer Cell Line Encyclopedia. The clinical relevance of these novel genes in LUAD was further examined by immunohistochemistry. We identified the overlapping differentially expressed genes (DEGs) in five independent microarray data sets from the Gene Expression Omnibus database ( GSE75037 , GSE85716 , GSE85841 , GSE63459 , and GSE32867 ). Using the criteria of |log (fold change)| ≥ 1 and P value <0.05, 167 genes were preliminarily validated as co-DEGs. Protein-protein interaction network analysis indicated that caveolin 1 (CAV1) and decorin (DCN) levels were significantly reduced and that these genes were the most promising predictive biomarkers for the occurrence and prognosis of LUAD. A cell proliferation assay indicated that overexpressed CAV1 and DCN could significantly inhibit the proliferation rate of A549 and H157 cells. Additionally, these two downregulated candidate genes were further verified by immunohistochemistry conducted on a LUAD tissue array and comprehensive bioinformatics analyses, including those using the Oncomine platform and the Cancer Cell Line Encyclopedia. Our study demonstrates low levels of CAV1 and DCN in LUAD. An understanding of their functional roles in LUAD biology would give us important insights that would be useful in further investigations.
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Affiliation(s)
- Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University , Changsha , China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University , Changsha , China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University , Changsha , China
| | - Long Qian
- Department of Pharmacy, Xiangya Hospital, Central South University , Changsha , China
| | - Shuangshuang Zeng
- Department of Pharmacy, Xiangya Hospital, Central South University , Changsha , China
| | - Yangying Zhou
- Department of Medical Oncology, Xiangya Hospital, Central South University , Changsha , China
| | - Xi Chen
- Department of Pharmacy, Xiangya Hospital, Central South University , Changsha , China
| | - Jie Wei
- Department of Pharmacy, Xiangya Hospital, Central South University , Changsha , China
| | - Zhicheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South University , Changsha , China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University , Changsha , China
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Kalli M, Minia A, Pliaka V, Fotis C, Alexopoulos LG, Stylianopoulos T. Solid stress-induced migration is mediated by GDF15 through Akt pathway activation in pancreatic cancer cells. Sci Rep 2019; 9:978. [PMID: 30700740 PMCID: PMC6353927 DOI: 10.1038/s41598-018-37425-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 12/06/2018] [Indexed: 12/29/2022] Open
Abstract
Solid stress is a biomechanical abnormality of the tumor microenvironment that plays a crucial role in tumor progression. When it is applied to cancer cells, solid stress hinders their proliferation rate and promotes cancer cell invasion and metastatic potential. However, the underlying mechanisms of how it is implicated in cancer metastasis is not yet fully understood. Here, we used two pancreatic cancer cell lines and an established in vitro system to study the effect of solid stress-induced signal transduction on pancreatic cancer cell migration as well as the mechanism involved. Our results show that the migratory ability of cells increases as a direct response to solid stress. We also found that Growth Differentiation Factor 15 (GDF15) expression and secretion is strongly upregulated in pancreatic cancer cells in response to mechanical compression. Performing a phosphoprotein screening, we identified that solid stress activates the Akt/CREB1 pathway to transcriptionally regulate GDF15 expression, which eventually promotes pancreatic cancer cell migration. Our results suggest a novel solid stress signal transduction mechanism bringing GDF15 to the centre of pancreatic tumor biology and rendering it a potential target for future anti-metastatic therapeutic innovations.
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Affiliation(s)
- Maria Kalli
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | | | | | - Christos Fotis
- Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece
| | - Leonidas G Alexopoulos
- ProtATonce Ltd, Athens, Greece.,Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
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Yu H, Song H, Ma Z, Ji W. Down-regulation of MiR-539 Indicates Poor Prognosis in Patients with Pancreatic Cancer. Open Life Sci 2019; 13:497-503. [PMID: 33817119 PMCID: PMC7874721 DOI: 10.1515/biol-2018-0059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 09/29/2018] [Indexed: 01/01/2023] Open
Abstract
It has been demonstrated that miR-539 plays an important role in the development and progression of tumors. The purpose of this study was to analyze the correlation between the expression level of miR-539 and the clinicopathological features and prognosis of patients with pancreatic cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression level of miR-539 in 60 patients with pancreatic cancer. It was found that miR-539 gene expression was down-regulated in pancreatic cancer compared with that in paracancerous tissues. In addition, the expression level of miR-539 was inversely correlated with tumor differentiation (poorly to moderately differentiated vs. well differentiated, P=0.006), lymph node metastasis (positive vs. negative, P=0.006), clinical stage (III-IV vs. I-II, P=0.002), CA199 (≥200 vs. <200, P=0.019) and distant metastasis (positive vs. negative, P=0.035). The survival time of pancreatic cancer patients with low expression of miR-539 was significantly shorter than that of patients with high expression of miR-539. Multivariate analysis suggested that miR-539 expression level was an independent prognostic indicator for patients with pancreatic cancer (P=0.025). Down-regulation of miR-539 may be a potentially unfavorable prognostic factor for patients with pancreatic cancer, and further studies are needed to confirm our conclusion in the future.
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Affiliation(s)
- Haibo Yu
- Research Institute of General Surgery, Nanjing General Hospital of Nanjing Military Region, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, PR China.,Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, P.R. China
| | - Hongliang Song
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, P.R. China
| | - Zhongwu Ma
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, P.R. China
| | - Wu Ji
- Research Institute of General Surgery, Nanjing General Hospital of Nanjing Military Region, the First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, PR China
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Screening and bioinformatics analysis of mRNA, long non-coding RNA and circular RNA expression profiles in mucoepidermoid carcinoma of salivary gland. Biochem Biophys Res Commun 2018; 508:66-71. [PMID: 30471855 DOI: 10.1016/j.bbrc.2018.11.102] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 11/15/2018] [Indexed: 01/16/2023]
Abstract
Mucoepidermoid carcinoma (MEC) of salivary gland is a disease characterized by high rate of diatant metastasis, and associated with poor outcomes. However, the molecular mechanisms underlying the MEC remain poorly understand. Here, we simultaneously detected, for the first time, the expression profiles of mRNAs, lncRNAs, and circRNAs in four pairs of MEC and matched non-carcinoma tissues by microarrays. A total of 3612 mRNA, 3091 lncRNAs, and 284 circRNAs were altered during the pathogenesis of MEC. The functions of these differentially expressed RNAs were predicted by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Co-expression networks of lncRNA-mRNA and circRNA-miRNA were conducted to uncovered the hidden ceRNA mechanisms. Moreover, NONHSAT154433.1 that associated with ADAM12 and hsa_circ_0012342 were further screened and confirmed using qRT-PCR analysis. In conclusion, this study provides a systematic perspective on the potential function of non-coding RNAs (ncRNAs) in the molecular mechanisms of MEC. Among these, NONHSAT154433.1 and hsa_circ_0012342 might be served as potential prognostic biomarkers and therapeutic target of MEC.
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da Silveira WA, Renaud L, Simpson J, Glen WB, Hazard ES, Chung D, Hardiman G. miRmapper: A Tool for Interpretation of miRNA⁻mRNA Interaction Networks. Genes (Basel) 2018; 9:genes9090458. [PMID: 30223528 PMCID: PMC6162471 DOI: 10.3390/genes9090458] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/07/2018] [Accepted: 09/07/2018] [Indexed: 12/11/2022] Open
Abstract
It is estimated that 30% of all genes in the mammalian cells are regulated by microRNA (miRNAs). The most relevant miRNAs in a cellular context are not necessarily those with the greatest change in expression levels between healthy and diseased tissue. Differentially expressed (DE) miRNAs that modulate a large number of messenger RNA (mRNA) transcripts ultimately have a greater influence in determining phenotypic outcomes and are more important in a global biological context than miRNAs that modulate just a few mRNA transcripts. Here, we describe the development of a tool, “miRmapper”, which identifies the most dominant miRNAs in a miRNA–mRNA network and recognizes similarities between miRNAs based on commonly regulated mRNAs. Using a list of miRNA–target gene interactions and a list of DE transcripts, miRmapper provides several outputs: (1) an adjacency matrix that is used to calculate miRNA similarity utilizing the Jaccard distance; (2) a dendrogram and (3) an identity heatmap displaying miRNA clusters based on their effect on mRNA expression; (4) a miRNA impact table and (5) a barplot that provides a visual illustration of this impact. We tested this tool using nonmetastatic and metastatic bladder cancer cell lines and demonstrated that the most relevant miRNAs in a cellular context are not necessarily those with the greatest fold change. Additionally, by exploiting the Jaccard distance, we unraveled novel cooperative interactions between miRNAs from independent families in regulating common target mRNAs; i.e., five of the top 10 miRNAs act in synergy.
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Affiliation(s)
- Willian A da Silveira
- Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
| | - Ludivine Renaud
- Division of Nephrology, Department of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
- Laboratory for Marine Systems Biology, Hollings Marine Laboratory, Charleston, SC 29412, USA.
| | - Jonathan Simpson
- Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
| | - William B Glen
- Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
| | - Edward S Hazard
- Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
- Academic Affairs Faculty, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
| | - Dongjun Chung
- Department of Public Health Sciences, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
| | - Gary Hardiman
- Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
- Division of Nephrology, Department of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
- Laboratory for Marine Systems Biology, Hollings Marine Laboratory, Charleston, SC 29412, USA.
- Department of Public Health Sciences, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
- Institute for Global Food Security, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, UK.
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Fransquet PD, Ryan J. Micro RNA as a potential blood-based epigenetic biomarker for Alzheimer's disease. Clin Biochem 2018; 58:5-14. [PMID: 29885309 DOI: 10.1016/j.clinbiochem.2018.05.020] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/17/2018] [Accepted: 05/31/2018] [Indexed: 12/13/2022]
Abstract
As the prevalence of Alzheimer's disease (AD) increases, the search for a definitive, easy to access diagnostic biomarker has become increasingly important. Micro RNA (miRNA), involved in the epigenetic regulation of protein synthesis, is a biological mark which varies in association with a number of disease states, possibly including AD. Here we comprehensively review methods and findings from 26 studies comparing the measurement of miRNA in blood between AD cases and controls. Thirteen of these studies used receiver operator characteristic (ROC) analysis to determine the diagnostic accuracy of identified miRNA to predict AD, and three studies did this with a machine learning approach. Of 8098 individually measured miRNAs, 23 that were differentially expressed between AD cases and controls were found to be significant in two or more studies. Only six of these were consistent in their direction of expression between studies (miR-107, miR-125b, miR-146a, miR-181c, miR-29b, and miR-342), and they were all shown to be down regulated in individuals with AD compared to controls. Of these directionally concordant miRNAs, the strongest evidence was for miR-107 which has also been shown in previous studies to be involved in the dysregulation of proteins involved in aspects of AD pathology, as well as being consistently downregulated in studies of AD brains. We conclude that imperative to the discovery of reliable and replicable miRNA biomarkers of AD, standardised methods of measurements, appropriate statistical analysis, utilization of large datasets with machine learning approaches, and comprehensive reporting of findings is urgently needed.
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Affiliation(s)
- Peter D Fransquet
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne 3004, Victoria, Australia; Disease Epigenetics, Murdoch Childrens Research Institute, and The University of Melbourne, Parkville, 3052, Victoria, Australia.
| | - Joanne Ryan
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne 3004, Victoria, Australia; Disease Epigenetics, Murdoch Childrens Research Institute, and The University of Melbourne, Parkville, 3052, Victoria, Australia; INSERM, U1061, Neuropsychiatrie, Recherche Clinique et Epidémiologique, Univ. Montpellier, Montpellier 34000, France
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Liu X, Weng Y, Liu P, Sui Z, Zhou L, Huang Y, Zhang L, Zhang Y, Tan X. Identification of PGAM1 as a putative therapeutic target for pancreatic ductal adenocarcinoma metastasis using quantitative proteomics. Onco Targets Ther 2018; 11:3345-3357. [PMID: 29922073 PMCID: PMC5995415 DOI: 10.2147/ott.s162470] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal cancer characterized by an extremely low survival rate because of early metastasis. Identifying satisfactory therapeutic targets associated with metastasis is crucial to improve the treatment effect of PDAC. Materials and methods In this research, we used stable isotope labeling by amino acids in cell culture, 1-dodecyl-3-methylimidazolium chloride-assisted sample preparation method preparing protein sample and nano-reversed-phase liquid chromatography-mass spectrometry/mass spectrometry analysis to perform the comparative proteomics of two homologous hamster pancreatic cancer cell lines that are different in metastatic ability: PC-1.0 (highly metastatic) and PC-1 (weakly metastatic). Verifications are through immunohistochemistry on clinical human PDAC pathologic tissues as well as by Western blot of human pancreatic cancer cell lines. siRNA silencing methods were used to study the effect of molecules on invasion and metastasis of pancreatic cancer cell lines. Results Bioinformatic analysis indicated that a total of 141 differentially expressed proteins (82 upregulated and 59 downregulated in PC-1.0 cells) were identified showing obviously differential expression (>1.5-fold change). These differentially expressed proteins were involved in a number of different biologic functions, metabolic pathways, and pathophysiologic processes. Phosphoglycerate mutase 1 (PGAM1) and HSPE1 are the top two upregulated proteins, and PDIA3 and CALR are the top two downregulated proteins in PC-1.0 cells compared to PC-1 cells. PGAM1 and HSPE1 showed higher expressions in PDAC tissue with clinical metastasis and highly metastatic pancreatic cancer cell lines PC-1.0 and Aspc-1. PDIA3 and CALR showed higher expressions in weakly metastatic pancreatic cancer cell lines PC-1 and Capan-2. The Western blot results were consistent with the MS quantification data. Silencing PGAM1 was found to decrease the migration and invasion of pancreatic cancer cell lines with statistical significance, especially in highly metastatic PC-1.0 and Aspc-1 cell lines. Conclusion These data indicated that PGAM1 may be a potential therapeutic target for PDAC metastasis.
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Affiliation(s)
- Xinlu Liu
- First Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, China
| | - Yejing Weng
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, China
| | - Peng Liu
- First Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, China
| | - Zhigang Sui
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, China
| | - Lei Zhou
- First Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, China
| | - Yinpeng Huang
- First Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, China
| | - Lihua Zhang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, China
| | - Yukui Zhang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, China
| | - Xiaodong Tan
- First Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, China
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Khor ES, Wong PF. Endothelial replicative senescence delayed by the inhibition of MTORC1 signaling involves MicroRNA-107. Int J Biochem Cell Biol 2018; 101:64-73. [PMID: 29857052 DOI: 10.1016/j.biocel.2018.05.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/22/2018] [Accepted: 05/29/2018] [Indexed: 01/01/2023]
Abstract
Accumulation of senescent endothelial cells can contribute to endothelium dysfunction. Suppression of MTOR signaling has been shown to delay senescence but the mechanism that underpins this effect, particularly one that involves miRNAs, remains to be further defined. This study sought to identify miRNAs involved in MTORC1-mediated inhibition of replicative senescence in endothelial cells. Pre-senescent HUVECs were prolonged treated with low dose rapamycin (1 nM), an MTOR inhibitor. Rapamycin treatment down-regulated the phosphorylated MTOR, RPS6 and 4EBP1 expressions, which confirmed MTORC1 suppression. Prolonged low dose rapamycin treatment has significantly reduced the percentage of senescence-associated beta galactosidase (SA-β gal) positively stained senescent cells and P16INK4A expression in these cells. On the contrary, the percentage of BrdU-labelled proliferating cells has significantly increased. RPTOR, a positive regulator of MTORC1 was knockdown using RPTOR siRNA to inhibit MTORC1 activation. RPTOR knockdown was evidenced by significant suppressions of RPTOR mRNA and protein expression levels. In these cells, the expression of miR-107 was down-regulated whereas miR-145-5p and miR-217 were up-regulated. Target gene prediction revealed PTEN as the target of miR-107 and this was confirmed by biotin pull-down assay. Over-expression of miR-107 has decreased PTEN expression, increased MTORC1 activity, induced cell cycle arrest at G0/G1 phase and up-regulated P16INK4A expression but mitigated tube formation. Collectively, our findings revealed that delayed endothelial replicative senescence caused by the inhibition of MTORC1 activation could be modulated by miR-107 via its influence on PTEN.
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Affiliation(s)
- Eng-Soon Khor
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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Functional Role of Non-Coding RNAs during Epithelial-To-Mesenchymal Transition. Noncoding RNA 2018; 4:ncrna4020014. [PMID: 29843425 PMCID: PMC6027143 DOI: 10.3390/ncrna4020014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/22/2018] [Accepted: 05/23/2018] [Indexed: 01/17/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell⁻cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.
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