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Lamberti MJ, Montico B, Ravo M, Nigro A, Giurato G, Iorio R, Tarallo R, Weisz A, Stellato C, Steffan A, Dolcetti R, Casolaro V, Faè DA, Dal Col J. Integration of miRNA:mRNA Co-Expression Revealed Crucial Mechanisms Modulated in Immunogenic Cancer Cell Death. Biomedicines 2022; 10:biomedicines10081896. [PMID: 36009442 PMCID: PMC9405340 DOI: 10.3390/biomedicines10081896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/23/2022] [Accepted: 07/29/2022] [Indexed: 11/21/2022] Open
Abstract
Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
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Affiliation(s)
- María Julia Lamberti
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
- INBIAS, CONICET-UNRC, Río Cuarto, Córdoba 5800, Argentina
- Correspondence: (M.J.L.); (J.D.C.); Tel.: +54-358-4676437 (M.J.L.); +39-089-965210 (J.D.C.)
| | - Barbara Montico
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, PN, Italy
| | - Maria Ravo
- Genomix Life Srl, 84081 Baronissi, SA, Italy
| | - Annunziata Nigro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
| | | | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
| | - Cristiana Stellato
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, PN, Italy
| | - Riccardo Dolcetti
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Vincenzo Casolaro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
| | - Damiana Antonia Faè
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, PN, Italy
| | - Jessica Dal Col
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, SA, Italy
- Correspondence: (M.J.L.); (J.D.C.); Tel.: +54-358-4676437 (M.J.L.); +39-089-965210 (J.D.C.)
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Low Expression of miR-491-3p Is Correlated with Lymph Node Metastasis in Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:7807956. [PMID: 35815280 PMCID: PMC9262502 DOI: 10.1155/2022/7807956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 02/03/2023]
Abstract
Objective MiR-491-3p, as a tumor suppressor miRNA, was found decreased in many solid tissues. In this study, we aim to investigate miR-491-3p expression in gastric cancer with or without lymph node metastasis (LNM). Methods GSE173215 dataset from Gene Expression Omnibus (GEO) was used to measure miRNA expression from tissue samples of gastric cancer patients. Moreover, gastric tumor tissues (non-LNM: n = 78; LNM: n = 68) were obtained to detect the miR-491-3p expression. Receiver operating characteristic (ROC) curve and Kaplan–Meier (KM) survival analysis, as well as Cox regression analysis, were performed to reveal the role of miR-491-3p in diagnosis and prognosis of gastric cancer. Results According to GSE173215 datasets (t = −11.25, adjust P value = 1.30E-06) and our clinical results (0.390 ± 0.193 vs. 0.562 ± 0.166, P < 0.005), the gastric cancer patients with LNM showed lower miR-491-3p expression than those without LNM, demonstrating a high diagnostic efficiency (sensitivity: 74.36%; specificity: 69.12%). In addition, both LNM and low miR-491-3p expression were correlated with the poor prognosis of gastric cancer. Furthermore, the LNM patient with low expression of miR-491-3p had the worse prognosis, but the non-LNM patient with high expression of miR-491-3p had the best prognosis. MiR-491-3p expression (HR = 0.003, 95%CI: 3.35E-04∼0.028) and LNM (HR = 2.326, 95%CI: 1.046∼5.173) were independent risk factors for gastric cancer. Conclusion Downregulated miR-491-3p expression was found in gastric cancer, being a high diagnostic efficiency and an independent risk factor for gastric cancer, especially in those having LNM.
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Mirzajani E, Vahidi S, Norollahi SE, Samadani AA. Novel biomarkers of microRNAs in gastric cancer; an overview from diagnosis to treatment. Microrna 2022; 11:12-24. [PMID: 35319404 DOI: 10.2174/2211536611666220322160242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/06/2021] [Accepted: 12/28/2021] [Indexed: 11/22/2022]
Abstract
The fourth frequent disease in the world and the second cause of cancer-related death is gastric cancer (GC). In this way, over 80% of diagnoses are made in the middle to advanced degrees of the disease, underscoring the requirement for innovative biomarkers that can be identified quickly. Meaningly, biomarkers that can complement endoscopic diagnosis and be used to detect patients with a high risk of GC are desperately needed. These biomarkers will allow for the accurate prediction of therapy response and prognosis in GC patients, as well as the development of an optimal treatment strategy for each individual. Conspicoiusly, microRNAs (miRNAs) and small noncoding RNA regulates the expression of target mRNA and thereby modifies critical biological mechanisms. According to the data, abnormally miRNAs expression in GC is linked to tumor growth, carcinogenesis, aggression and distant metastasis. Importantly, miRNA expression patterns and next-generation sequencing (NGS) can also be applied to analyze kinds of tissues and cancers. Given the high death rates and poor prognosis of GC, and the absence of a clinical diagnostic factor that is adequately sensitive to GC, research into novel sensitive and specific markers for GC diagnosis is critical. In this review,we evaluate the latest research findings that suggest the feasibility and clinical utility of miRNAs in GC.
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Affiliation(s)
- Ebrahim Mirzajani
- Department of Biochemistry, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Sogand Vahidi
- Clinical Research Development Unit of Poursina Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Clinical Research Development Unit of Poursina Hospital, Guilan University of Medical Sciences, Rasht, Iran
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Chen Q, Lin L, Xiong B, Yang W, Huang J, Shi H, Wang Z. MiR-873-5p targets THUMPD1 to inhibit gastric cancer cell behavior and chemoresistance. J Gastrointest Oncol 2021; 12:2061-2072. [PMID: 34790374 DOI: 10.21037/jgo-21-641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Background Gastric cancer is one of the most common gastrointestinal tumors. Evidence has pointed to the fact that miRNAs play critical roles in the occurrence, development, and metastasis of gastric cancer by regulating cell proliferation, differentiation, apoptosis, and invasion. Methods In this study, first the relationship of miR-873-5p level and tissues types/LN(+/-)/metastasis(+/-)/tumor size was analysis, respectively. Second, the CCK8 and Transwell assay was used to determine the proliferation, invasion and migration of GC cells transfected with overexpression-/low expression-miR-873-5p. Third, the cell viability were analysis in the GC cells transfected with overexpression-/low expression-miR-873-5p treatment with different chemotherapy drugs. Fourth, the target gene of miR-873-5p was predicted using bioinformation methods. Fifth, the relationship of miR-873-5p with target gene-THUMPD1 were explored by using Wb and luciferase activity assay, et al. Results We confirmed that miR-873-5p was negatively correlated with GC including tumor size, LN metastasis, distant metastasis. The miR-873-5p enhanced the sensitivity of Doxorubicin/Fluorouracil and cisplatin. The THUMPD1 was the target gene of miR-873-5p. Moreover, miR-873-5p could target the THUMPD1 axis so as to inhibit gastric cancer cell behavior as well as chemoresistance. Conclusions MiR-873-5p plays a role in regulating cell behavior as well as regulating chemoresistance in gastric cancer. In addition, THUMPD1, as a downstream molecule of miR-873-5p, plays an important role in the cell behavior and chemoresistance of gastric cancer. The research first confirmed that miR-873-5p could inhibit gastric cancer cell behavior and chemoresistance by targeting the THUMPD1.
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Affiliation(s)
- Qinggui Chen
- Department of General Surgery, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Li Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Boliang Xiong
- Department of Radiotherapy, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Wensheng Yang
- Department of Pathology, Chenggong Hospital, Xiamen University, Xiamen, China
| | - Junli Huang
- Department of General Surgery, Chenggong Hospital, Xiamen University, Xiamen, China
| | - Huibo Shi
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation, Wuhan, China
| | - Zhenfa Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Xiamen, China
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Dos Santos MP, Pereira JN, De Labio RW, Carneiro LC, Pontes JC, Barbosa MS, Smith MDAC, Payão SLM, Rasmussen LT. Decrease of miR-125a-5p in Gastritis and Gastric Cancer and Its Possible Association with H. pylori. J Gastrointest Cancer 2021; 52:569-574. [PMID: 32504357 DOI: 10.1007/s12029-020-00432-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The aim of this study was to evaluate the expression of miR-125a-5p in patients with dyspeptic symptoms and gastric cancer, correlating them with the development of this cancer and H. pylori. METHODS Patients were divided in groups according to histopathological analysis (control, gastritis, and cancer groups). Polymerase chain reaction was performed to detect H. pylori and real-time quantitative PCR to determine miR-125a-5p expression. RESULTS H. pylori was detected in 44% of the patients, with prevalence in the gastritis and cancer groups. A statistically significant decrease of miR-125a-5p expression was found in the control positive (p = 0.0183*), gastritis positive (p = 0.0380*), and cancer positive (p = 0.0288*) groups when compared with the control negative group. CONCLUSION We suggest that decreased expression of the miRNA-125a-5p associated with the presence of the H. pylori is an important mechanism in gastric diseases and could be a possible marker for early diagnosis of gastric cancer.
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Affiliation(s)
- Mônica Pezenatto Dos Santos
- Genetics Laboratory, Marília Medical School (FAMEMA), Lourival Freire, 240, Bairro Fragata, Marília, São Paulo, CEP 17519-050, Brazil
| | - Jéssica Nunes Pereira
- Genetics Laboratory, Marília Medical School (FAMEMA), Lourival Freire, 240, Bairro Fragata, Marília, São Paulo, CEP 17519-050, Brazil
| | - Roger Willian De Labio
- Genetics Laboratory, Marília Medical School (FAMEMA), Lourival Freire, 240, Bairro Fragata, Marília, São Paulo, CEP 17519-050, Brazil
| | - Lilian Carla Carneiro
- Institute of Tropical Pathology and Public Health, Federal University of Goiás (UFG), Goiânia, Goiás, Brazil
| | - Jaqueline Correia Pontes
- Institute of Tropical Pathology and Public Health, Federal University of Goiás (UFG), Goiânia, Goiás, Brazil
| | - Mônica Santiago Barbosa
- Institute of Tropical Pathology and Public Health, Federal University of Goiás (UFG), Goiânia, Goiás, Brazil
| | | | - Spencer Luíz Marques Payão
- Genetics Laboratory, Marília Medical School (FAMEMA), Lourival Freire, 240, Bairro Fragata, Marília, São Paulo, CEP 17519-050, Brazil
| | - Lucas Trevizani Rasmussen
- Biochemistry Department, Marília Medical School (FAMEMA), Lourival Freire, 240, Bairro Fragata, Marília, São Paulo, CEP 17519-050, Brazil.
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Dang Y, Liu T, Yan J, Reinhardt JD, Yin C, Ye F, Zhang G. Gastric cancer proliferation and invasion is reduced by macrocalyxin C via activation of the miR-212-3p/Sox6 Pathway. Cell Signal 2020; 66:109430. [PMID: 31726103 DOI: 10.1016/j.cellsig.2019.109430] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/03/2019] [Accepted: 09/26/2019] [Indexed: 01/09/2023]
Abstract
Gastric cancer is a malignancy of very poor prognosis and survival rates. Macrocalyxin C is a Chinese herb-derived diterpenoid compound that has been postulated to possess anti-cancer characteristics. Gastic cell viability and stage of cell cycle were assessed using CCK8 assay and flow cytometry, respectively. Cell migration and invation were assessed using the wound healing and Transwell assays. Rate of apoptosis was determined via AV/PI-staining. Athymic nude mice xenograft models were used to evaluate the in vivo efficacy of macrocalyxin C. Western blot, luciferase experiments, cell transfection and real-time PCR allowed further study into the activation of the miR-212-3p/Sox6 pathway during macrocalyxin C treatment. We conclude that macrocalyxin C may halt the proliferation of gastric malignancies through alteration of cell invasion, apoptosis, progression through the cell cycle and cell growth. The macrocalyxin C→miR-212-3p┤Sox6 signal pathway was identified to be involved in Sox6 attenuation through augmentation of miR-212-3p values.
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Affiliation(s)
- Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - TingYu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China; Department of Gastroenterology, Affiliated Zhongshan Hospital of fudan university, Shanghai, China
| | - Jin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - Jan D Reinhardt
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, Sichuan Province, China; Epidemiology of Functioning, Swiss Paraplegic Research, Nottwil, Switzerland
| | - Chengqiang Yin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China; Department of Gastroenterology, Sir Run Run Hospital Affiliated with Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Feng Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China.
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Chen W, Song J, Bian H, Yang X, Xie X, Zhu Q, Qin C, Qi J. The functions and targets of miR-212 as a potential biomarker of cancer diagnosis and therapy. J Cell Mol Med 2020; 24:2392-2401. [PMID: 31930653 PMCID: PMC7028855 DOI: 10.1111/jcmm.14966] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 12/17/2019] [Accepted: 12/22/2019] [Indexed: 12/14/2022] Open
Abstract
Cancer is a major health problem worldwide. An increasing number of researchers are studying the diagnosis, therapy and mechanisms underlying the development and progression of cancer. The study of noncoding RNA has attracted a lot of attention in recent years. It was found that frequent alterations of miRNA expression not only have various functions in cancer but also that miRNAs can act as clinical markers of diagnosis, stage and progression of cancer. MiR-212 is an important example of miRNAs involved in cancer. According to recent studies, miR-212 may serve as an oncogene or tumour suppressor by influencing different targets or pathways during the oncogenesis and the development and metastasis of cancer. Its deregulation may serve as a marker for the diagnosis or prognosis of cancer. In addition, it was recently reported that miR-212 was related to the sensitivity or resistance of cancer cells to chemotherapy or radiotherapy. Here, we summarize the current understanding of miR-212 functions in cancer by describing the relevant signalling pathways and targets. The role of miR-212 as a biomarker and its therapeutic potential in cancer is also described. The aim of this review was to identify new methods for the diagnosis and treatment of human cancers.
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Affiliation(s)
- Wenjun Chen
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Departments of Gastroenterology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Qingdao, China
| | - Jing Song
- Departments of Gastroenterology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Qingdao, China
| | - Hongjun Bian
- Departments of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xia Yang
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiaoyu Xie
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Qiang Zhu
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Chengyong Qin
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Jianni Qi
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Marques MM, Evangelista AF, Macedo T, Vieira RADC, Scapulatempo-Neto C, Reis RM, Carvalho AL, da Silva IDCG. Expression of tumor suppressors miR-195 and let-7a as potential biomarkers of invasive breast cancer. Clinics (Sao Paulo) 2018; 73:e184. [PMID: 29995098 PMCID: PMC6024513 DOI: 10.6061/clinics/2018/e184] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 01/05/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. Some miRNAs, including let-7a and miR-195, have been described as tumor suppressors. However, the roles of these microRNAs in breast cancer progression remain controversial. The aim of this study is to evaluate miR-195 and let-7a expression as potential biomarkers of invasive breast cancer. METHODS In the present study, 200 individuals were separated into three groups: (i) 72 women constituting the control group who were selected according to rigorous and well-established criteria; (ii) 56 patients with benign breast tumors; and (iii) 72 patients with malignant breast cancers of different clinical stages. The miR-195 and let-7a expression levels in serum were evaluated by real-time PCR. The results were assessed alone and in combination, and the analysis included an estimation of sensitivity and specificity in ROC curves. RESULTS Compared with the benign and control groups, both microRNAs were downregulated in the malignant breast cancer patient group. Compared with the malignant group, the combination of both biomarkers in the control and benign groups showed good sensitivity and specificity in the serum with AUCs of 0.75 and 0.72, respectively. The biomarker combination for the control group versus the malignant group exhibited a better sensitivity and specificity than for the benign group versus the malignant group. CONCLUSION These findings support the evidence that the analysis of miR-195 and let-7a can be used as a non-invasive biomarker for breast cancer detection.
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Affiliation(s)
- Marcia M. Marques
- Centro de Pesquisa em Oncologia Molecular (CPOM), Hospital de Cancer de Barretos, Barretos, SP, BR
- Faculdade de Ciencias da Saude de Barretos Dr Paulo Prata (FACISB), Barretos, SP, BR
- *Corresponding author. E-mail:
| | - Adriane F. Evangelista
- Centro de Pesquisa em Oncologia Molecular (CPOM), Hospital de Cancer de Barretos, Barretos, SP, BR
| | - Taciane Macedo
- Centro de Pesquisa em Oncologia Molecular (CPOM), Hospital de Cancer de Barretos, Barretos, SP, BR
| | | | | | - Rui M. Reis
- Centro de Pesquisa em Oncologia Molecular (CPOM), Hospital de Cancer de Barretos, Barretos, SP, BR
- Instituto de Pesquisa de Ciencias da Vida e Saude, Universidade de Minho, Braga, Portugal
- Laboratorio Associado ICVS/3B’s, Braga, Portugal
| | - André L. Carvalho
- Centro de Pesquisa em Oncologia Molecular (CPOM), Hospital de Cancer de Barretos, Barretos, SP, BR
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Huang J, He Y, Mcleod HL, Xie Y, Xiao D, Hu H, Chen P, Shen L, Zeng S, Yin X, Ge J, Li L, Tang L, Ma J, Chen Z. miR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/ β-catenin/EMT signaling cascade in gastric cancer. BMC Cancer 2017; 17:886. [PMID: 29273006 PMCID: PMC5741943 DOI: 10.1186/s12885-017-3875-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 12/04/2017] [Indexed: 02/08/2023] Open
Abstract
Background EphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, this study aims to identify microRNAs that target it and serve as key regulators of gastric carcinogenesis. Methods We identified several potential microRNAs targeting EphA2 by bioinformatics websites and then analyzed the role of miR-302b in modulating EphA2 in vitro and in vivo of GC, and it’s mechanism. Results Our analysis identified miR-302b, a novel regulator of EphA2, as one of the most significantly downregulated microRNA (miRNA) in GC tissues. Overexpression of miR-302b impaired GC cell migratory and invasive properties robustly and suppressed cell proliferation by arresting cells at G0–G1 phase in vitro. miR-302b exhibited anti-tumor activity by reversing EphA2 regulation, which relayed a signaling transduction cascade that attenuated the functions of N-cadherin, β-catenin, and Snail (markers of Wnt/β-catenin and epithelial-mesenchymal transition, EMT). This modulation of EphA2 also had distinct effects on cell proliferation and migration in GC in vivo. Conclusions miR-302b serves as a critical suppressor of GC cell tumorigenesis and metastasis by targeting the EphA2/Wnt/β-catenin/EMT pathway. Electronic supplementary material The online version of this article (10.1186/s12885-017-3875-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yijing He
- Department of Dermatology, XiangYa Hospital, Central South University, Changsha, 410008, China
| | - Howard L Mcleod
- Department of Clinical Pharmacology, XiangYa Hospital, Central South University, Changsha, 410008, China.,Hunan Key Laboratory of Pharmacogenetics, Changsha, 410008, China.,Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, 33612, USA
| | - Yanchun Xie
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Huabin Hu
- The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China
| | - Pan Chen
- Department of Hepatobiliary Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Xianli Yin
- Department of gastroenterology and urology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Jie Ge
- Department of General Surgery, Xiangya Hospital of Central South University, No.87 Xiangya Road, Changsha, 410008, People's Republic of China
| | - Li Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Lanhua Tang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jian Ma
- Cancer Research Institute, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Central South University, No.138 Tongzipo Road, Changsha, China.
| | - Zihua Chen
- Department of General Surgery, Xiangya Hospital of Central South University, No.87 Xiangya Road, Changsha, 410008, People's Republic of China.
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10
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Liang L, Zhang L, Cui D, Yang D. Identification of the key miRNAs associated with survival time in stomach adenocarcinoma. Oncol Lett 2017; 14:4563-4572. [PMID: 29085454 PMCID: PMC5649651 DOI: 10.3892/ol.2017.6792] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 06/15/2017] [Indexed: 12/12/2022] Open
Abstract
Stomach adenocarcinoma (STAD) is one of the leading causes of cancer morbidity and mortality worldwide. The present study aimed to identify the microRNAs associated with STAD survival time. The clinical information and microarray miRNA and mRNA expression profiles of STAD patients were downloaded from The Cancer Genome Atlas. Differential expression (DE) analysis was performed to identify DEmiRNAs and DEmRNAs in STAD. The DEmiRNAs associated with the survival time of patients with STAD were identified through DE analysis, negative correlation pair analysis, miRNA target gene prediction, univariate Cox regression analysis and Kaplan-Meier analysis. The functions of the target genes of the DEmiRNAs were predicted with Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A total of 355 DEmiRNAs and 1,722 DEmRNAs were identified between STAD and normal tissues. A total of 5 DEmiRNAs were identified to be associated with STAD survival, including 4 risk-associated DEmiRNAs (miR-30a, -143, -145 and -133b) and 1 protective DEmiRNA (miR-135b). The target DEmRNAs were significantly enriched for DNA metabolic process in the biological process GO category, and in KEGG cell cycle signaling pathways. Kaplan-Meier curves indicated that the overall survival time in the miR-30a, -143, -145 and -133b high expression groups was significantly shorter than that in the low expression groups, whereas the survival time was prolonged in the miR-135b high expression group compared with that in the low expression group. Therefore, miR-30a, -143, -145, -133b and -135b may be involved in the tumorigenesis and development of STAD, and may be potential biomarkers for its early diagnosis and prognosis.
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Affiliation(s)
- Li Liang
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Lingling Zhang
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Dejun Cui
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Daping Yang
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
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11
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Luo Z, Li X, Zhao Z, Yang X, Xiao S, Zhou Y. MicroRNA-146a affects the chemotherapeutic sensitivity and prognosis of advanced gastric cancer through the regulation of LIN52. Oncol Lett 2016; 13:1386-1392. [PMID: 28454266 PMCID: PMC5403335 DOI: 10.3892/ol.2016.5536] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 11/07/2016] [Indexed: 12/12/2022] Open
Abstract
The present study aimed to evaluate the correlation between the expression of microRNA-146a (miR-146a) and its target gene, LIN52, in advanced gastric cancer, and determine their potential effects on chemotherapeutic sensitivity and prognosis. Total RNA was extracted from 93 tissue samples of advanced gastric cancer and corresponding adjacent non-tumor tissues to quantify the relative expression levels of miR-146a using reverse transcription-quantitative polymerase chain reaction analysis. The expression of LIN52 was detected in tumors and normal tissues using immunohistochemical analysis. Correlation analysis was performed to assess the correlation between the expression of miR-146a and LIN52 and clinicopathological parameters of gastric cancer, including clinical diagnostic specificity, clinical tumor-necrosis-metastasis staging, lymph node metastasis, differentiation grade, chemotherapeutic sensitivity and prognosis. The expression of miR-146a in advanced gastric cancer tissues was lower, compared with that in the adjacent non-tumor tissues, and was negatively correlated with lymph node metastasis (P<0.05). Gastric cancer tissues with a low expression level of miR146a exhibited an increased expression level of LIN52 (P<0.05). Receiver operating characteristic curve regression analysis showed that miR-146a had 98% sensitivity in distinguishing gastric cancer tissues and adjacent non-tumor tissues. A high expression of miR-146a in gastric cancer was associated with improved treatment efficacy in patients. The chemotherapeutic sensitivity of patients with tumors expressing high levels of miR-146a was significantly higher, compared with that of patients with tumors expressing low levels of miR-146a (P<0.05). The expression of miR-146a was low in advanced gastric cancer tissues. As a tumor suppressor gene in advanced gastric cancer, miR-146a had a significant negative correlation with LIN52. High expression levels of miR-146a in advanced gastric cancer tissue may be associated with improved treatment efficacy of chemotherapy, suggesting that miR-146a may be a molecular marker for the diagnosis, prediction of treatment efficacy and prognosis of advanced gastric cancer.
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Affiliation(s)
- Zhifen Luo
- Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, P.R. China
| | - Xiqing Li
- Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, P.R. China
| | - Zunlan Zhao
- Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, P.R. China
| | - Xinglong Yang
- Cancer Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Shengjun Xiao
- Department of Pathology, Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
| | - Yun Zhou
- Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, P.R. China
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12
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da Silva Oliveira KC, Thomaz Araújo TM, Albuquerque CI, Barata GA, Gigek CO, Leal MF, Wisnieski F, Rodrigues Mello Junior FA, Khayat AS, de Assumpção PP, Rodriguez Burbano RM, Smith MC, Calcagno DQ. Role of miRNAs and their potential to be useful as diagnostic and prognostic biomarkers in gastric cancer. World J Gastroenterol 2016; 22:7951-7962. [PMID: 27672290 PMCID: PMC5028809 DOI: 10.3748/wjg.v22.i35.7951] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 06/14/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Alterations in epigenetic control of gene expression play an important role in many diseases, including gastric cancer. Many studies have identified a large number of upregulated oncogenic miRNAs and downregulated tumour-suppressor miRNAs in this type of cancer. In this review, we provide an overview of the role of miRNAs, pointing to their potential to be useful as diagnostic and/or prognostic biomarkers in gastric cancer. Moreover, we discuss the influence of polymorphisms and epigenetic modifications on miRNA activity.
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13
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Rossi AFT, Cadamuro ACT, Biselli-Périco JM, Leite KRM, Severino FE, Reis PP, Cordeiro JA, Silva AE. Interaction between inflammatory mediators and miRNAs in Helicobacter pylori infection. Cell Microbiol 2016; 18:1444-58. [PMID: 26945693 PMCID: PMC5074252 DOI: 10.1111/cmi.12587] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 02/12/2016] [Accepted: 02/29/2016] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori cause chronic inflammation favouring gastric carcinogenesis, and its eradication may prevent malignant transformation. We evaluated whether H. pylori infection and its eradication modify the expression of inflammatory mediators in patients with chronic gastritis. Furthermore, we assessed whether microRNAs modulate inflammatory pathways induced by H. pylori and identified miRNA–gene interaction networks. mRNA and protein expression of TNFA, IL6, IL1B, IL12A, IL2 and TGFBRII and miRNAs miR‐103a‐3p, miR‐181c‐5p, miR‐370‐3p, miR‐375 and miR‐223‐3p were evaluated in tissue samples from 20 patients with chronic gastritis H. pylori negative (Hp−) and 31 H. pylori positive (Hp+), before and three months after bacterium eradication therapy, in comparison with a pool of Hp− normal gastric mucosa. Our results showed that H. pylori infection leads to up‐regulation of TNFA, IL6, IL12A and IL2 and down‐regulation of miRNAs. Bacterium eradication reduces the expression of TNFA and IL6 and up‐regulates TGFBRII and all investigated miRNAs, except miR‐223‐3p. Moreover, transcriptional profiles of inflammatory mediators and miRNAs after eradication are different from the non‐infected group. Deregulated miRNA–mRNA interaction networks were observed in the Hp+ group before and after eradication. Therefore, miRNAs modulated cytokine expression in the presence of H. pylori and after its eradication, suggesting that miRNAs participate in the pathological process triggered by H. pylori in the gastric mucosa.
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Affiliation(s)
- Ana Flávia Teixeira Rossi
- UNESP, São Paulo State University, Department of Biology, Rua Cristóvão Colombo, 2265, São José do Rio Preto, SP, Brazil
| | - Aline Cristina Targa Cadamuro
- UNESP, São Paulo State University, Department of Biology, Rua Cristóvão Colombo, 2265, São José do Rio Preto, SP, Brazil
| | - Joice Matos Biselli-Périco
- UNESP, São Paulo State University, Department of Biology, Rua Cristóvão Colombo, 2265, São José do Rio Preto, SP, Brazil
| | - Kátia Ramos Moreira Leite
- USP, São Paulo University, Faculty of Medicine, Department of Surgery, Avenida Dr. Arnaldo, 455, São Paulo, SP, Brazil
| | - Fábio Eduardo Severino
- UNESP, São Paulo State University, Faculty of Medicine, Department of Surgery and Orthopedics, Avenida Prof. Montenegro, Botucatu, SP, Brazil
| | - Patricia P Reis
- UNESP, São Paulo State University, Faculty of Medicine, Department of Surgery and Orthopedics, Avenida Prof. Montenegro, Botucatu, SP, Brazil
| | - José Antonio Cordeiro
- UNESP, São Paulo State University, Department of Biology, Rua Cristóvão Colombo, 2265, São José do Rio Preto, SP, Brazil
| | - Ana Elizabete Silva
- UNESP, São Paulo State University, Department of Biology, Rua Cristóvão Colombo, 2265, São José do Rio Preto, SP, Brazil.
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14
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Chen YJ, Wu H, Zhu JM, Li XD, Luo SW, Dong L, Liu TT, Shen XZ. MicroRNA-18a modulates P53 expression by targeting IRF2 in gastric cancer patients. J Gastroenterol Hepatol 2016; 31:155-63. [PMID: 26173586 DOI: 10.1111/jgh.13041] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/25/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM MicroRNA-18a (miR-18a) has been reported to be upregulated in gastric cancer (GC) tissues compared with normal gastric tissues. However, little is known about its prognostic value and biological roles. METHODS In this study, miR-18a expression in gastric adenocarcinoma (GAC) tissues and adjacent non-tumor tissues was validated by in situ hybridization, and the predictive values of miR-18a were explored. The biological roles of miR-18a and the underlying signal pathway were investigated in GC cell lines. RESULTS Overexpressed intra-tumoral miR-18a was associated with poor survival rate and was an independent prognostic factor for overall survival rate (P < 0.001) in GC patients. Forced expression of miR-18a remarkably enhanced cell proliferation, migration, and invasion in GC cells, while inhibition of miR-18a caused the opposite effects. Further study showed that miR-18a suppressed the expression of interferon regulatory factor 2 (IRF2) by directly binding to its 3'-untranslated region. Moreover, miR-18a expression levels are inversely correlated with IRF2 in human GC tissues. Western blot showed that forced expression of miR-18a could not only downregulate the expression of IRF2, but also inhibit the expression of P53, suggesting that IRF2 might play as a tumor suppressor by regulating P53 signaling in GC. CONCLUSION miR-18a modulated P53 expression by directly targeting IRF2 and had a high predictive value for prognosis of GAC patients. These results may lead to identification of therapeutic candidates of GC.
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Affiliation(s)
- Yan-Jie Chen
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hao Wu
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xiao-Dan Li
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Si-Wei Luo
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ling Dong
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
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15
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Yan C, Yu J, Kang W, Liu Y, Ma Z, Zhou L. miR-935 suppresses gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression. Biochem Biophys Res Commun 2015; 470:68-74. [PMID: 26742429 DOI: 10.1016/j.bbrc.2015.12.116] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 12/26/2015] [Indexed: 01/05/2023]
Abstract
Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis. Expression of microRNAs (miRNAs) has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. The function of miR-935 has never been reported in cancer before. We found, using microRNA array, that expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. We also identified Notch1 as a direct target of miR-935. Knockdown of Notch1 reduced proliferation, migration/invasion of GSRCC cells, and overexpression Notch1's activated form (Notch intracellular domain) could rescue miR-935's tumor suppressive effect on GSRCC. Expression of miR-935 was lower in gastric carcinoma tissue than in paired normal tissue samples, and lower in GSRCC than in non-GSRCC. Our results demonstrate the inverse correlation between the expression of miR-935 and Notch1 in gastric tissues. We conclude that miR-935 inhibits gastric carcinoma cell proliferation, migration and invasion by targeting Notch1, suggesting potential applications of the miR-935-Notch1 pathway in gastric cancer clinical diagnosis and therapeutics, especially in gastric signet ring cell carcinoma.
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Affiliation(s)
- Chao Yan
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Jianchun Yu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
| | - Weiming Kang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Yuqin Liu
- Cell Culture Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Zhiqiang Ma
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
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16
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Liu L, Ye JX, Qin YZ, Chen QH, Ge LY. Evaluation of miR-29c, miR-124, miR-135a and miR-148a in predicting lymph node metastasis and tumor stage of gastric cancer. Int J Clin Exp Med 2015; 8:22227-22236. [PMID: 26885198 PMCID: PMC4729984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 12/12/2015] [Indexed: 06/05/2023]
Abstract
MicroRNAs (miRNAs) are small noncoding RNA that have diverse functions in different biological process. The aim of this study was to evaluate the predictive ability of miR-29c, miR-124, miR-135a and miR-148a for lymph node metastasis (LNM) and tumor stage in gastric cancer. The expression of these miRNAs was detected and quantitated in gastric cancer tissues and in adjacent normal tissues from 60 patients by quantitative real-time reverse transcription-polymerase chain reaction. CT imaging and clinicopathologic characteristics of these patients were performed. The result of this study was that these miRNAs were down-regulated in gastric cancer tissues; The low expression of miR-124 and miR-135a in LNM group and tumor III-IV stages (P < 0.01) presented the potential correlation with LNM and tumor stage; The two miRNAs were highly correlated with r = 0.730. Receiver operating characteristic curve analysis showed that miR-124 had better predictive ability to identify LNM and tumor stage. It could discriminate non-LNM from LNM with 80.0% sensitivity and 80.0% specificity and discriminate tumor Ι-II stages from tumor III-IV stages with 71.9% sensitivity and 75.0% specificity at the best cut-off value of 0.0125. Compared with CT imaging, miR-124 had similar specificity (0.800 versus 0.900, P = 0.508) but higher sensitivity (0.800 versus 0.500, P = 0.022) for lymph node assessment; Combined of miR-124 and CT imaging, The sensitivity and specificity of assessing LNM were raised to 83.3% and 90.0% respectively. Taken together, miR-124 may be a predictor for LNM and tumor stage in gastric cancer.
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Affiliation(s)
- Li Liu
- Department of Medical Oncology, The Affiliated Tumor Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, P. R. China
| | - Jia-Xiang Ye
- Department of Medical Oncology, The Affiliated Tumor Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, P. R. China
| | - Yu-Zhou Qin
- Department of Gastrointestinal Surgery, The Affiliated Tumor Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, P. R. China
| | - Qi-Huang Chen
- Department of Medical Oncology, The Affiliated Tumor Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, P. R. China
| | - Lian-Ying Ge
- Department of Medical Oncology, The Affiliated Tumor Hospital of Guangxi Medical UniversityNanning 530021, Guangxi, P. R. China
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17
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Yan C, Yu J, Liu Y, Kang W, Ma Z, Zhou L. MiR-32 promotes gastric carcinoma tumorigenesis by targeting Kruppel-like factor 4. Biochem Biophys Res Commun 2015; 467:913-20. [PMID: 26471298 DOI: 10.1016/j.bbrc.2015.10.044] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 10/08/2015] [Indexed: 12/23/2022]
Abstract
Gastric cancer (GC) is a prevalent malignant cancer worldwide and is highly lethal because of its fast growth. Currently, the clinical therapy options for GC remain limited. MiR-32 has been reported as an oncogenic microRNA in many cancers, but its role in GC is unclear. Here, we found that miR-32 was overexpressed in GC tissues compared with adjacent normal tissue, and miR-32 was higher in GC patients' plasma compared with healthy individuals. Furthermore, we have identified miR-32 to be oncogenic, by promoting gastric cell proliferation, migration and invasion. We also identified Kruppel-like factor 4 (KLF4) as a direct target of miR-32. Knockdown of KLF4 promoted proliferation, migration and invasion of GC cells. We conclude that miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4, suggesting that the miR-32-KLF4 pathway may be useful in clinical diagnosis and therapeutics.
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Affiliation(s)
- Chao Yan
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Jianchun Yu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
| | - Yuqin Liu
- Cell Culture Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Weiming Kang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Zhiqiang Ma
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
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18
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Li D, Li Z, Xiong J, Gong B, Zhang G, Cao C, Jie Z, Liu Y, Cao Y, Yan Y, Xiong H, Qiu L, Yang M, Chen H, Jiang S, Yang X, Chen H. MicroRNA-212 functions as an epigenetic-silenced tumor suppressor involving in tumor metastasis and invasion of gastric cancer through down-regulating PXN expression. Am J Cancer Res 2015; 5:2980-2997. [PMID: 26693054 PMCID: PMC4656725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/17/2015] [Indexed: 06/05/2023] Open
Abstract
Altered expression of paxillin (PXN) is closely linked to the pathogenesis progression, metastasis and prognosis of different malignancies including gastric cancer (GC). Epigenetic silencing of tumor-suppressive microRNAs (miRNAs) is a crucial component of the mechanism underlying activation of oncogenes in tumor. To screen for epigenetically silenced miRNAs which target PXN in GC, we performed bioinformatics algorithms and real-time PCR analysis, and identified miR-212 as the optimum candidate gene. A luciferase reporter gene assay validated that miR-212 directly targets the 3'UTR region of PXN. Importantly, miR-212 levels were inversely correlated with PXN expression in GC cell lines and clinical tumor tissues. The use of miR-212 minics decrease PXN mRNA and protein level in GC cell lines. Moreover, low expression of miR-212 and its promoter hypermethylation were causally related and were associated with aggressive tumor phenotype and adverse prognosis in GC. Restoring mir-212 expression by exogenous mirprecursor molecules transfection or reexpression of endogenous miR-212 treated by 5-aza-2'-deoxycytidine (5-aza) can exert similar effect that reduce GC cells invasion and metastasis abilities in vitro by interacting PXN gene. In addition, 5-aza-induced PXN reduction could be partically blocked by miR-212 inhibitor, resulting in a reversal of weankening cell migration and invasion ability of 5-aza. A rescue experiment and a loss-of-function experiment in vitro and vivo showed that PXN restoration rescues migration and invasion phenotype in miR-212 overexpressed GC cell lines and PXN knockdown blocks GC cells migration and invasion in the presence miR-212 inhibitors. Taken together, our results clearly show that overexpression of PXN induced by methylationsuppressed miR-212 promotes tumor metastasis and invasion, and regulation of miR-212 expression may be a novel therapeutic strategy for gastric cancer.
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Affiliation(s)
- Daojiang Li
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
- Nanchang University Medical CollegeNanchang 330000, Jiangxi Province, China
| | - Zhengrong Li
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
| | - Jianbo Xiong
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
- Nanchang University Medical CollegeNanchang 330000, Jiangxi Province, China
| | - Binbin Gong
- Nanchang University Medical CollegeNanchang 330000, Jiangxi Province, China
| | - Guoyang Zhang
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
- Nanchang University Medical CollegeNanchang 330000, Jiangxi Province, China
| | - Chao Cao
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
- Nanchang University Medical CollegeNanchang 330000, Jiangxi Province, China
| | - Zhigang Jie
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
| | - Yi Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
| | - Yi Cao
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Nanchang UniversityNanchang 330000, Jiangxi Province, China
| | - Yufeng Yan
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang UniversityNanchang 330006, Jiangxi Province, China
| | - Hong Xiong
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang UniversityNanchang 330006, Jiangxi Province, China
| | - Lingyu Qiu
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang UniversityNanchang 330006, Jiangxi Province, China
| | - Miantian Yang
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang UniversityNanchang 330006, Jiangxi Province, China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College, Nanchang UniversityBayi Road 603, Nanchang 330006, China
| | - Shuping Jiang
- Department of Histology and Embryology, Medical College, Nanchang UniversityBayi Road 603, Nanchang 330006, China
| | - Xiongwen Yang
- Nanchang University Medical CollegeNanchang 330000, Jiangxi Province, China
| | - Heping Chen
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang UniversityNanchang 330006, Jiangxi Province, China
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19
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Tu H, Wei G, Cai Q, Chen X, Sun Z, Cheng C, Zhang L, Feng Y, Zhou H, Zhou B, Zeng T. MicroRNA-212 inhibits hepatocellular carcinoma cell proliferation and induces apoptosis by targeting FOXA1. Onco Targets Ther 2015; 8:2227-35. [PMID: 26347321 PMCID: PMC4556035 DOI: 10.2147/ott.s87976] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
MircroRNA-212 (miR-212) is proposed as a novel tumor-related miRNA and has been found to be significantly deregulated in human cancers. In this study, the miR-212 expression was found to be obviously downregulated in hepatocellular carcinoma (HCC) tissues as compared with adjacent nontumor tissues. Clinical association analysis indicated that low expression of miR-212 was prominently correlated with poor prognostic features of HCC, including high AFP level, large tumor size, high Edmondson-Steiner grading, and advanced tumor-node-metastasis tumor stage. Furthermore, the miR-212 expression was an independent prognostic marker for predicting both 5-year overall survival and disease-free survival of HCC patients. Our in vitro studies showed that upregulation of miR-212 inhibited cell proliferation and induced apoptosis in HepG2 cells. On the contrary, downregulation of miR-212 promoted cell proliferation and suppressed apoptosis in Huh7 cells. Interestingly, we found that upregulation of miR-212 decreased FOXA1 expression in HepG2 cells. Significantly, FOXA1 was identified as a direct target of miR-212 in HCC. FOXA1 was downregulated in HCC tissues as compared with noncancerous tissues. An inverse correlation between FOXA1 and miR-212 expression was observed in HCC tissues. Notably, FOXA1 knockdown inhibited cell proliferation and induced apoptosis in HepG2 cells. In conclusion, miR-212 is a potent prognostic marker and may suppress HCC tumor growth by inhibiting FOXA1 expression.
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Affiliation(s)
- Huahua Tu
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Gang Wei
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Qinghe Cai
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Xianxiang Chen
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Zequn Sun
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Caitao Cheng
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Linfei Zhang
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Yong Feng
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Huadong Zhou
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Bo Zhou
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Tiancai Zeng
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
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Jiang C, Chen X, Alattar M, Wei J, Liu H. MicroRNAs in tumorigenesis, metastasis, diagnosis and prognosis of gastric cancer. Cancer Gene Ther 2015; 22:291-301. [DOI: 10.1038/cgt.2015.19] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 03/15/2015] [Accepted: 03/16/2015] [Indexed: 02/07/2023]
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The clinical value of ncRNAs in gastric cancer: a systematic review and meta-analyses. Tumour Biol 2015; 36:4017-25. [DOI: 10.1007/s13277-015-3411-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 03/30/2015] [Indexed: 12/28/2022] Open
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22
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Zhao XM, Liu KQ, Zhu G, He F, Duval B, Richer JM, Huang DS, Jiang CJ, Hao JK, Chen L. Identifying cancer-related microRNAs based on gene expression data. Bioinformatics 2014; 31:1226-34. [DOI: 10.1093/bioinformatics/btu811] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 12/04/2014] [Indexed: 12/19/2022] Open
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Guo L, Bai H, Zou D, Hong T, Liu J, Huang J, He P, Zhou Q, He J. The role of microRNA-133b and its target gene FSCN1 in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:99. [PMID: 25433493 PMCID: PMC4272783 DOI: 10.1186/s13046-014-0099-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 11/17/2014] [Indexed: 11/23/2022]
Abstract
Background Increasing evidences have documented that microRNAs (miRNAs) act as oncogenes or tumor suppressors in gastric cancer (GC). In this study, we aimed to investigate the expression of miR-133b in a large number of GC samples and elucidate its role in GC carcinogenesis and the detailed mechanism. Methods We used Taqman probe stem-loop real-time PCR to accurately measure the levels of miR-133b in 100 pairs of gastric cancer tissues and the adjacent non-neoplastic tissues. miR-133b mimics were overexpressed in GC cell lines, miR-133b inhibitors were also introduced in GES cells to investigate its role on regulating cell proliferation, cell migration and cell invasion. The target of miR-133b was identified by luciferase reporter assay and western blot. Fascin actin-bundling protein 1 (FSCN1) siRNA was used to achieve the knockdown of FSCN1 in GC cells and to investigate its role on modulating GC cell proliferation and invasion. Results miR-133b was significantly down-regulated in GC cell lines and in GC tissues compared with adjacent normal tissues. Moreover, lower-level of miR-133b was also associated with venous invasion and a more aggressive tumor phenotype. Re-introduction of miR-133b in GC cells can inhibit cell proliferation, cell migration and invasion. In contrary, knockdown of miR-133b in GES cells can promote cell proliferation and invasion. Further investigation indicated that miR-133b targeted FSCN1 in GC cells and knockdown of FSCN1 can also inhibit GC cell growth and invasion. Conclusion Our findings demonstrated that miR-133b was significantly down-regulated in GC tissues and exerted its tumor suppressor role in GC cells. The investigation of the detailed mechanism showed that miR-133b directly targeted FSCN1 which functioned as an oncogenic gene in GC cells. These results suggested that miR-133b can be developed as a new diagnostic marker or therapeutic target for GC.
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Affiliation(s)
- Lihua Guo
- School of Computer and Information Technology, Shangyuan Residence, Haidian District, Beijing, 100044, China. .,College of Life Sciences and Bioengineering, Beijing Jiaotong University, Shangyuan Residence, Haidian District, Beijing, 100044, China.
| | - Hua Bai
- Department of Ophthalmology, General Hospital of Bei Jing Command of PLA, #5 Nanmencang, DongCheng District, Beijing, 100700, China.
| | - Dongling Zou
- Department of Gynecologic Oncology, Chongqing Cancer Institute, Chongqing, 400030, China.
| | - Tao Hong
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Shangyuan Residence, Haidian District, Beijing, 100044, China.
| | - Jie Liu
- School of Computer and Information Technology, Shangyuan Residence, Haidian District, Beijing, 100044, China.
| | - Jiaqiang Huang
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Shangyuan Residence, Haidian District, Beijing, 100044, China.
| | - Pengfei He
- National Institutes for Food and Drug Control, No.2 Tiantan Xi Li, Beijing, 100050, China.
| | - Qi Zhou
- Department of Gynecologic Oncology, Chongqing Cancer Institute, Chongqing, 400030, China.
| | - Jinsheng He
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Shangyuan Residence, Haidian District, Beijing, 100044, China.
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Han C, Yu H, Zhang L, Li X, Feng Y, Xin H. MicroRNAs used as novel biomarkers for detecting cancer metastasis. Tumour Biol 2014; 36:1755-62. [PMID: 25366141 DOI: 10.1007/s13277-014-2777-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 10/23/2014] [Indexed: 01/07/2023] Open
Abstract
The low survival rates of cancers are primarily due to late diagnosis and metastasis. Discriminating the metastasis is a crucial factor for prognosis and improving the survival rate of cancer patients. MicroRNAs (miRNAs) can regulate the expression of hundreds of downstream genes, which has a broad effect on the regulation of the whole cell cycle. Accumulating studies have found that the aberrant expression of miRNAs is associated with cancer genesis. The aim of this study is to evaluate the diagnostic value of miRNAs in detecting cancer metastasis. Medline, PubMed, Embase, and CNKI were searched for relevant articles. Sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR) and diagnostic odds ratio (DOR), the summary receiver operator characteristic (SROC) curve and the calculated AUC (area under the SROC curve) were applied to explore the diagnostic accuracy of miRNAs in metastasis. Seven hundred seventy-one metastatic cancer patients and 552 non-metastatic cancer controls from 14 articles were involved in our meta-analysis. A sensitivity of 0.75 (95% confidence interval (CI), 0.72-0.79) and a specificity of 0.80 (95% CI, 0.76-0.84) were observed from metastatic patients and non-metastatic controls in the combined analysis. And the AUC was 0.83 (95% CI, 0.79-0.86). In addition, results from subgroup analyses suggested that a higher diagnostic value for metastasis was acquired in tissue sample other than blood sample (sensitivity, 0.82 versus 0.73; specificity, 0.84 versus 0.79; PLR, 5.0 versus 3.5; NLR, 0.22 versus 0.34; DOR, 23 versus 10; AUC, 0.88 versus 0.80). In summary, this meta-analysis proved the relatively high diagnostic value of miRNA in metastasis, which might be applied as a novel screening tool to detect metastasis along with other biomarkers. We also illustrated that tissue-based miRNAs may have a better diagnostic accuracy than blood-based miRNAs.
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Affiliation(s)
- Chunshan Han
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, Jilin, China
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Liu HS, Xiao HS. MicroRNAs as potential biomarkers for gastric cancer. World J Gastroenterol 2014; 20:12007-12017. [PMID: 25232237 PMCID: PMC4161788 DOI: 10.3748/wjg.v20.i34.12007] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 05/06/2014] [Accepted: 06/13/2014] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancer-related death. More than 80% of diagnoses occur at the middle to late stage of the disease, highlighting an urgent need for novel biomarkers detectable at earlier stages. Recently, aberrantly expressed microRNAs (miRNAs) have received a great deal of attention as potential sensitive and accurate biomarkers for cancer diagnosis and prognosis. This review summarizes the current knowledge about potential miRNA biomarkers for gastric cancer that have been reported in the publicly available literature between 2008 and 2013. Available evidence indicates that aberrantly expressed miRNAs in gastric cancer correlate with tumorigenesis, tumor proliferation, distant metastasis and invasion. Furthermore, tissue and cancer types can be classified using miRNA expression profiles and next-generation sequencing. As miRNAs in plasma/serum are well protected from RNases, they remain stable under harsh conditions. Thus, potential functions of these circulating miRNAs can be deduced and may implicate their diagnostic value in cancer detection. Circulating miRNAs, as well as tissue miRNAs, may allow for the detection of gastric cancer at an early stage, prediction of prognosis, and monitoring of recurrence and/or lymph node metastasis. Taken together, the data suggest that the participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic and prognostic tests for gastric cancer.
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26
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MicroRNA and signaling pathways in gastric cancer. Cancer Gene Ther 2014; 21:305-16. [PMID: 25060632 DOI: 10.1038/cgt.2014.37] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) function as either oncogenes or tumor suppressors by inhibiting the expression of target genes, some of which are either directly or indirectly involved with canonical signaling pathways. The relationship between miRNAs and signaling pathways in gastric cancer is extremely complicated. In this paper, we determined the pathogenic mechanism of gastric cancer related to miRNA expression based on recent high-quality studies and then clarified the regulation network of miRNA expression and the correlated functions of these miRNAs during the progression of gastric cancer. We try to illustrate the correlation between the expression of miRNAs and outcomes of patients with gastric cancer. Understanding this will allow us to take a big step forward in the treatment of gastric cancer.
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Liu Z, Zhang G, Li J, Liu J, Lv P. The tumor-suppressive microRNA-135b targets c-myc in osteoscarcoma. PLoS One 2014; 9:e102621. [PMID: 25025684 PMCID: PMC4099365 DOI: 10.1371/journal.pone.0102621] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 06/20/2014] [Indexed: 01/30/2023] Open
Abstract
Osteosarcoma is the most common primary tumor of the bone. It leads to many deaths because of its rapid proliferation and metastasis. Recent studies have shown that microRNAs are important gene regulators that are involved in various cancer-related processes. In this study, we found that miR-135b was down-regulated in both osteoscarcoma patient tumor tissues and osteoscarcoma cell lines in comparison to paired adjacent non-tumor bone tissue. We observed that a lower level of miR-135b was associated with metastasis. The ectopic expression of miR-135b markedly suppressed osteoscarcoma cell proliferation, migration, and invasion. Conversely, the inhibition of miR-135b expression dramatically accelerated cell proliferation, migration, and invasion. The forced expression of miR-135b in osteosarcoma cells resulted in a significant reduction in the protein level of c-Myc and repressed the activity of a luciferase reporter that contained the 3′-untranslated region of the c-Myc mRNA. These effects were abolished by the mutation of the predicted miR-135b-binding site, which indicates that c-Myc may be a miR-135b target gene. Moreover, the ectopic expression of c-Myc partially reversed the inhibition of cell proliferation and invasion that was caused by miR-135b. These data therefore suggest that miR-135b may function as a tumor suppressor to regulate osteosarcoma cell proliferation and invasion through a mechanism that targets the c-Myc oncogene. These findings indicate that miR-135b may play a role in the pathogenesis of osteosarcoma.
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Affiliation(s)
- Zheng Liu
- Department of Orthopedic Surgery, Peking University Shougang Hospital, Beijing, China
- * E-mail:
| | - Guangwu Zhang
- Department of Orthopedic Surgery, Peking University Shougang Hospital, Beijing, China
| | - Jian Li
- Department of Orthopedic Surgery, Peking University Shougang Hospital, Beijing, China
| | - Jiabang Liu
- Department of Orthopedic Surgery, Peking University Shougang Hospital, Beijing, China
| | - Pengfeng Lv
- Department of Orthopedic Surgery, Peking University Shougang Hospital, Beijing, China
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Zeng T, Li G. MicroRNA‑10a enhances the metastatic potential of cervical cancer cells by targeting phosphatase and tensin homologue. Mol Med Rep 2014; 10:1377-82. [PMID: 25018014 DOI: 10.3892/mmr.2014.2370] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 04/24/2014] [Indexed: 11/05/2022] Open
Abstract
Cervical cancer is one of the leading causes of cancer‑related mortality worldwide. Previously, the upregulation of microRNA (miR)‑10a has been identified in human cervical cancer. The present study firstly demonstrated that miR‑10a was markedly upregulated in primary tumor tissues in patients with positive lymph node metastasis (LN+) compared with negative (LN‑) by quantitative polymerase chain reaction. miR‑10a mimics markedly enhanced cervical cancer cell migration and invasion abilities, and accordingly the miR‑10a inhibitor suppressed those functions. Furthermore, these data suggested that the phosphatase and tensin homologue (PTEN) was inhibited by miR‑10a through an miR‑10a binding site within the 3'‑untranslated region of PTEN at the posttranscriptional level, and that miR‑10a mimics promoted nuclear translocation of β‑catenin. Therefore, it was concluded that the overexpression of miR‑10a contributes to metastasis in cervical cancer by targeting PTEN. miR‑10a may therefore be used clinically as a molecular marker for patients with cervical cancer lymph node metastasis.
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Affiliation(s)
- Tianhe Zeng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430023, P.R. China
| | - Guiling Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430023, P.R. China
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A functional variant at miR-132-3p, miR-212-3p, and miR-361-5p binding site in CD80 gene alters susceptibility to gastric cancer in a Chinese Han population. Med Oncol 2014; 31:60. [PMID: 24981235 DOI: 10.1007/s12032-014-0060-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 05/29/2014] [Indexed: 12/22/2022]
Abstract
A number of single-nucleotide polymorphisms within the 3'-UTR of genes have been shown to relate to the occurrence of cancers. In this study, by using polymerase chain reaction-restriction fragment length analysis method, we determined an SNP rs1599795 in the 3'-UTR of CD80 gene in 183 gastric cancer patients and 348 healthy controls. Statistical analysis results showed that SNP rs1599795 genotypes were significantly correlated with the risk of gastric cancer. Compared with the AA homozygotes, the TA heterozygotes were significantly more prevalent in the patients (OR 1.44, 95 % CI 0.98-2.11) with a larger tumor size (P = 0.001), deeper infiltration (P = 1.5 × 10(-5)), higher possibility of lymph node metastasis (P = 0.003), and more in the late stage (TNM stage III and IV; P = 0.003); the TT homozygotes had larger tumor size (P = 0.001) and lower degree of differentiation (P = 2.2 × 10(-4)). Dual-luciferase reporter assays showed that miR-132-3p, miR-212-3p, and miR-361-5p inhibited the expression of CD80 through binding with the CD80 3'-UTR, and this inhibitory role of miR-132-3p, miR-212-3p, and miR-361-5p was impacted by rs1599795. Our findings have shown that the SNP rs1599795 in CD80 3'-UTR, through disrupting the regulatory role of miR-132-3p, miR-212-3p, and miR-361-5p in CD80 expression, contributed to the occurrence of gastric cancer.
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Zhao Y, Huang J, Zhang L, Qu Y, Li J, Yu B, Yan M, Yu Y, Liu B, Zhu Z. MiR-133b is frequently decreased in gastric cancer and its overexpression reduces the metastatic potential of gastric cancer cells. BMC Cancer 2014; 14:34. [PMID: 24443799 PMCID: PMC3925791 DOI: 10.1186/1471-2407-14-34] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 01/16/2014] [Indexed: 12/18/2022] Open
Abstract
Background Emerging evidence has shown that microRNAs are involved in gastric cancer development and progression. Here we examine the role of miR-133b in gastric cancer. Methods Quantitative real-time PCR analysis was performed in 140 patient gastric cancer tissues and 8 gastric cancer cell lines. The effects of miR-133b in gastric cancer cells metastasis were examined by scratch assay, transwell migration and matrigel invasion. In vivo effects of miR-133b were examined in an intraperitoneal mouse tumor model. Targets of miR-133b were predicted by bioinformatics tools and validated by luciferase reporter analyses, western blot, and quantitative real-time PCR. Results MiR-133b was significantly downregulated in 70% (98/140) of gastric cancer patients. Expression of miR-133b was negatively correlated with lymph node metastasis of gastric cancer in patients. Similarly, the expression of miR-133b was significantly lower in seven tested gastric cancer cell lines than in the immortalized non-cancerous GES-1 gastric epithelial cells. Overexpression of miR-133b markedly inhibited metastasis of gastric cancer cells in vitro and in vivo. Moreover, the transcriptional factor Gli1 was identified as a direct target for miR-133b. Level of Gli1 protein but not mRNA was decreased by miR-133b. Activity of luciferase with Gli1 3′-untranslated region was markedly decreased by miR-133b in gastric cancer cells. Gli1 target genes, OPN and Zeb2, were also inhibited by miR133b. Conclusions MiR-133b is frequently decreased in gastric cancer. Overexpression of miR-133b inhibits cell metastasis in vitro and in vivo partly by directly suppressing expression of Gli1 protein. These results suggested that miR-133b plays an important role in gastric cancer metastasis.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road, Shanghai 200025, People's Republic of China.
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Song F, Yang D, Liu B, Guo Y, Zheng H, Li L, Wang T, Yu J, Zhao Y, Niu R, Liang H, Winkler H, Zhang W, Hao X, Chen K. Integrated microRNA network analyses identify a poor-prognosis subtype of gastric cancer characterized by the miR-200 family. Clin Cancer Res 2013; 20:878-89. [PMID: 24352645 DOI: 10.1158/1078-0432.ccr-13-1844] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE Our aim was to investigate whether microRNAs can predict the clinical outcome of patients with gastric cancer. We used integrated analysis of microRNA and mRNA expression profiles to identify gastric cancer microRNA subtypes and their underlying regulatory scenarios. EXPERIMENTAL DESIGN MicroRNA-based gastric cancer subtypes were identified by consensus clustering analysis of microRNA profiles of 90 gastric cancer tissues. Activated pathways in the subtypes were identified by gene expression profiles. Further integrated analysis was conducted to model a microRNA regulatory network for each subtype. RNA and protein expression were analyzed by RT-PCR and tissue microarray, respectively, in a cohort of 385 gastric cancer cases (including the 90 cases for profiling) to validate the key microRNAs and targets in the network. Both in vitro and in vivo experiments were carried out to further validate the findings. RESULTS MicroRNA profiles of 90 gastric cancer cases identified two microRNA subtypes significantly associated with survival. The poor-prognosis gastric cancer microRNA subtype was characterized by overexpression of epithelial-to-mesenchymal transition (EMT) markers. This gastric cancer "mesenchymal subtype" was further validated in a patient cohort comprising 385 cases. Integrated analysis identified a key microRNA regulatory network likely driving the gastric cancer mesenchymal subtype. Three of the microRNAs (miR-200c, miR-200b, and miR-125b) targeting the most genes in the network were significantly associated with survival. Functional experiments demonstrated that miR-200b suppressed ZEB1, augmented E-cadherin, inhibited cell migration, and suppressed tumor growth in a mouse model. CONCLUSIONS We have uncovered a key microRNA regulatory network that defines the mesenchymal gastric cancer subtype significantly associated with poor overall survival in gastric cancer.
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Affiliation(s)
- Fengju Song
- Authors' Affiliations: Departments of Epidemiology and Biostatistics, Immunology, and Gastric Cancer, TMUCIH-J&J Joint Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital; Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, PR China; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Janssen Research and Development, a Division of Janssen Pharmaceutica, Beerse, Belgium
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Su Y, Li X, Ji W, Sun B, Xu C, Li Z, Qian G, Su C. Small molecule with big role: MicroRNAs in cancer metastatic microenvironments. Cancer Lett 2013; 344:147-56. [PMID: 24184826 DOI: 10.1016/j.canlet.2013.10.024] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 10/22/2013] [Accepted: 10/24/2013] [Indexed: 12/19/2022]
Abstract
Cancer metastasis is closely related to tumor cell microenvironments. Cancer cells and stromal cells interact with one another through extracellular matrix (ECM) and jointly participate in establishing the microenvironments. However, many questions remain to be addressed, in particular, a crucial question is which messengers mediate the mutual interaction and regulation between cancer cells and stromal cells. MicroRNAs (miRNAs), as oncogenic and oncosuppressor genes, regulate the expression and function of their related target genes to affect the biological behaviors of cancer cells and stromal cells, which may play an important role in cancer metastasis. Many miRNAs associated with cancer metastasis have been identified. The molecules of miRNAs are small and relatively easy to be secreted into extracellular microenvironments and devoured by nearby cells. As the regulatory messengers between cells, the secreted miRNAs function to regulate cancer cell proliferation, migration, intercellular communication and stromal modification, thereby helping cancer cells to establish their microenvironments for metastasis. In conclusion, miRNAs are small molecules, but they play a powerful role in regulating cancer metastatic ability by construction and modification of microenvironments.
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Affiliation(s)
- Yinghan Su
- Department of Biology, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China
| | - Xiaoya Li
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Weidan Ji
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
| | - Can Xu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Guojun Qian
- Department of Minimal Invasion Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China.
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China.
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Kim SY, Jeon TY, Choi CI, Kim DH, Kim DH, Kim GH, Ryu DY, Lee BE, Kim HH. Validation of circulating miRNA biomarkers for predicting lymph node metastasis in gastric cancer. J Mol Diagn 2013; 15:661-669. [PMID: 23806809 DOI: 10.1016/j.jmoldx.2013.04.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 03/17/2013] [Accepted: 04/02/2013] [Indexed: 12/14/2022] Open
Abstract
We validated candidate biomarkers using circulating miRNAs by analyzing serum miRNA concentrations from patients with gastric cancer (GC) to predict lymph node (LN) metastasis. In a pilot study, serum levels of miR-21, miR-27a, miR-106b, miR-146a, miR-148a, miR-223, and miR-433 were compared in 10 healthy donors, 16 LN-positive patients with GC, and 15 LN-negative patients with GC. Then, we compared the level of three miRNAs (miR-21, miR-146a, and miR-148a) with the total of 79 GC patients with or without LN metastasis. In the pilot study, miR-21, miR-27a, miR-106b, miR-146a, miR-148a, and miR-223 concentrations from LN-positive patients with GC were significantly different from those of LN-negative patients with GC (P < 0.001, P = 0.003, P = 0.033, P < 0.001, P <0.001, and P = 0.017, respectively). In the validation study, levels of miR-21, miR-146a, and miR-148a increased as pN stage increased (P < 0.001, P = 0.001, and P < 0.001, respectively). Levels of the miRNAs were significantly different between pN0 and pN0 in the pT1 group (P = 0.013, P = 0.004, and P = 0.035, respectively) and among clinical stages (P = 0.001, P = 0.002, and P < 0.001, respectively). No differences in miRNA levels were observed by pT stage, Lauren's classification, sex, or age. Serum concentrations of miR-21, miR-146a, and miR-148a were closely associated with GC pN stage. These serum miRNA levels could be biomarker candidates to predict the presence of LN metastasis.
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Affiliation(s)
- Shine Young Kim
- Department of Clinical Laboratory Medicine, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea
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Abstract
The great majority of cancer deaths are due to metastasis, which remains a poorly understood pathological process. The formation of a metastasis reflects a succession of complex steps leading to the macroscopic outgrowth of disseminated tumor cells at the secondary site. In the past 5 years, certain microRNAs (miRNAs) have been shown to regulate either a single step or multiple steps of metastasis, doing so by downregulating the expression of their target genes. In this review, we discuss recent studies on the functions and molecular mechanisms of miRNAs in regulating epithelial-mesenchymal transition (EMT) and cancer metastasis.
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Deng H, Guo Y, Song H, Xiao B, Sun W, Liu Z, Yu X, Xia T, Cui L, Guo J. MicroRNA-195 and microRNA-378 mediate tumor growth suppression by epigenetical regulation in gastric cancer. Gene 2013; 518:351-9. [PMID: 23333942 DOI: 10.1016/j.gene.2012.12.103] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 10/30/2012] [Accepted: 12/24/2012] [Indexed: 12/19/2022]
Abstract
The epigenetic regulation of microRNAs is one of several mechanisms underlying carcinogenesis. We found that microRNA-195 (miR-195) and microRNA-378 (miR-378) were significantly down-regulated in gastric cancer tissues and gastric cancer cell lines. The expression of miR-195 and miR-378 in gastric cancer cells was significantly restored by 5-aza-dC, a demethylation reagent. The low expression of miR-195 and miR-378 was closely related to the presence of promoter CpG island methylation. Treatment with miR-195/miR-378 mimics strikingly suppressed the growth of gastric cancer cells whereas promoted the growth of normal gastric epithelial cells. In contrast, administration of miR-195/miR-378 inhibitors significantly prevented the growth of normal gastric epithelial cells. Expression of cyclin-dependent kinase 6 and vascular endothelial growth factor was down-regulated by exogenous miR-195 and miR-378, respectively. In conclusion, miR-195 and miR-378 are abnormally expressed and epigenetically regulated in gastric cancer cell lines and tissues via the suppression of CDK6 and VEGF signaling, suggesting that miR-195 and miR-378 have tumor suppressor properties in gastric cancer.
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Affiliation(s)
- Hongxia Deng
- Department of Biochemistry and Molecular Biology, and Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211, China
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Rodríguez RE. Morphine and microRNA Activity: Is There a Relation with Addiction? Front Genet 2012; 3:223. [PMID: 23162566 PMCID: PMC3494017 DOI: 10.3389/fgene.2012.00223] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 10/06/2012] [Indexed: 12/19/2022] Open
Abstract
When we talk about drug addiction, we are really dealing with an extremely complex system in which there still remain many unknowns and where many empty spaces or missing links are still present. Recent studies have identified changes in the expression profiles of several specific miRNAs which affect the interactions between these molecules and their targets in various illnesses, including addiction, and which may serve as valuable targets for more efficient therapies. In this review, we summarize results which clearly demonstrate that several morphine-related miRNAs have roles in the mechanisms that define addiction. In this regard, morphine has been shown to have an important role in the regulation of different miRNAs, such as miR-let-7 [which works as a mediator of the movement of the mu opioid receptor (MOR) mRNA into P-bodies, leading to translational repression], miR-23b (involved in linking MOR expression and morphine treatment at the post-transcriptional level), and miR-190 (a key post-transcriptional repressor of neurogenic differentiation, NeuroD). Fentanyl increases NeuroD levels by reducing the amount of miR-190, but morphine does not affect the levels of NeuroD. We also discuss the relationship between morphine, miRNAs, and the immune system, based on the discovery that morphine treatment of monocytes led to a decrease in several anti-HIV miRNAs (mir-28, 125b, 150, and 382). This review is centered on miR-133b and its possible involvement in addiction through the effects of morphine. We establish the importance of miR-133b as a regulatory factor by summarizing its activity in different pathological processes, especially cancer. Using the zebrafish as a research model, we discuss the relationship between mir-133b, the dopaminergic system, and morphine, considering: (1) that morphine modulates the expression of miR-133b and of its target transcript Pitx3, (2) the role of the zebrafish mu opioid receptor (zfMOR) in morphine-induced regulation of miR-133b, which depends on ERK1/2, (3) that morphine regulates miR-133b in hippocampal neurons, and (4) the role of delta opioid receptors in morphine-induced regulation of miR-133b. We conclude that the control of miR-133b levels may be a mechanism for the development of addiction to morphine, or other drugs of abuse that increase dopaminergic levels in the extracellular space. These results show that miR-133b is a possible new target for the design of new treatments against addictive disorders.
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Affiliation(s)
- Raquel E Rodríguez
- Department of Biochemistry and Molecular Biology, Institute of Neuroscience, University of Salamanca Salamanca, Spain
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MAO JIANHUA, ZHOU RONGPING, PENG AIFEN, LIU ZHILI, HUANG SHANHU, LONG XINHUA, SHU YONG. microRNA-195 suppresses osteosarcoma cell invasion and migration in vitro by targeting FASN. Oncol Lett 2012; 4:1125-1129. [PMID: 23162665 PMCID: PMC3499598 DOI: 10.3892/ol.2012.863] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 08/08/2012] [Indexed: 12/22/2022] Open
Abstract
microRNAs are involved in different cancer-related processes. miR-195, one of the miR-16/15/195/424/497 family members, has been shown to act as a tumor suppressor during tumorigenesis. However, the function of miR-195 in osteosarcoma is still unclear. In our study, the miR-195 expression level was upregulated in osteosarcoma cells, by transfection with miR-195, and the fatty acid synthase (FASN) mRNA and protein expression levels were measured by RT-PCR and western blotting. Cell migration and invasion was measured using wound healing migration and Transwell invasion assays. We found that the upregulation of miR-195 greatly decreased cell invasion and the migration of U2OS. We also identified that FASN may be a direct target of miR-195 by the luciferase activity assay. These findings provide evidence that miR-195 plays a key role in inhibiting osteosarcoma cell migration and invasion through targeting FASN, and strongly suggest that exogenous miR-195 may have therapeutic value in treating osteosarcoma.
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Affiliation(s)
- JIAN HUA MAO
- Department of Orthopedics, First Affiliated Hospital of Nanchang University
| | - RONG PING ZHOU
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University
| | - AI FEN PENG
- School of Humanities, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006,
P.R. China
| | - ZHI LI LIU
- Department of Orthopedics, First Affiliated Hospital of Nanchang University
| | - SHAN HU HUANG
- Department of Orthopedics, First Affiliated Hospital of Nanchang University
| | - XIN HUA LONG
- Department of Orthopedics, First Affiliated Hospital of Nanchang University
| | - YONG SHU
- Department of Orthopedics, First Affiliated Hospital of Nanchang University
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Nohata N, Hanazawa T, Enokida H, Seki N. microRNA-1/133a and microRNA-206/133b clusters: dysregulation and functional roles in human cancers. Oncotarget 2012; 3:9-21. [PMID: 22308266 PMCID: PMC3292888 DOI: 10.18632/oncotarget.424] [Citation(s) in RCA: 197] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
MicroRNAs (miRNAs) are endogenous short non-coding RNA molecules that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. A growing body of evidence suggests that miRNAs are aberrantly expressed in many human cancers and that they play significant roles in the initiation, development and metastasis of human cancers. Genome-wide miRNA expression signatures provide information on the aberrant expression of miRNAs in cancers rapidly and precisely. Recently, studies from our group and others revealed that microRNA-1 (miR-1), microRNA-133a (miR-133a), microRNA-133b (miR-133b) and microRNA-206 (miR-206) are frequently downregulated in various types of cancers. Interestingly, miR-1-1/miR-133a-2, miR-1-2/miR-133a-1, and miR-206/miR-133b form homologous clusters in three different chromosomal regions of the human genome – 20q13.33, 18q11.2 and 6p12.2, respectively. Here we review recent findings on the aberrant expression and functional significance of the miR-1/miR-133a and miR-206/miR-133b clusters in human cancers.
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Affiliation(s)
- Nijiro Nohata
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan
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Lopez-Camarillo C, Marchat LA, Arechaga-Ocampo E, Perez-Plasencia C, del Moral-Hernandez O, Castaneda-Ortiz EJ, Rodriguez-Cuevas S. MetastamiRs: non-coding MicroRNAs driving cancer invasion and metastasis. Int J Mol Sci 2012; 13:1347-1379. [PMID: 22408395 PMCID: PMC3291964 DOI: 10.3390/ijms13021347] [Citation(s) in RCA: 50] [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: 11/28/2011] [Revised: 01/09/2012] [Accepted: 01/09/2012] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that function as negative regulators of gene expression by either inhibiting translation or inducing deadenylation-dependent degradation of target transcripts. Notably, deregulation of miRNAs expression is associated with the initiation and progression of human cancers where they act as oncogenes or tumor suppressors contributing to tumorigenesis. Abnormal miRNA expression may provide potential diagnostic and prognostic tumor biomarkers and new therapeutic targets in cancer. Recently, several miRNAs have been shown to initiate invasion and metastasis by targeting multiple proteins that are major players in these cellular events, thus they have been denominated as metastamiRs. Here, we present a review of the current knowledge of miRNAs in cancer with a special focus on metastamiRs. In addition we discuss their potential use as novel specific markers for cancer progression.
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Affiliation(s)
- Cesar Lopez-Camarillo
- Genomics Sciences Program, Oncogenomics and Cancer Proteomics Laboratory, Autonomous University of Mexico City, Avenue San Lorenzo 290, 03100, Mexico; E-Mail:
| | - Laurence A. Marchat
- Biotechnology Program, Institutional Program of Molecular Biomedicine, National School of Medicine and Homeopathy of the National Polytechnic Institute, Guillermo Massieu Helguera 239, 07320, Mexico; E-Mail:
| | - Elena Arechaga-Ocampo
- Carcinogenesis Laboratory, National Institute of Cancerology, Avenue San Fernando 22, 14080, Mexico; E-Mail:
| | - Carlos Perez-Plasencia
- Massive Sequencing Unit, National Institute of Cancerology, Avenue San Fernando 22, 14080, Mexico; E-Mail:
- Genomics Laboratory, FES-I, UBIMED, National Autonomous University of Mexico, Avenue de los Barrios 1, 54090, Mexico
| | - Oscar del Moral-Hernandez
- Academic Unit of Biological Chemistry Sciences, Molecular Biomedicine Laboratory, Autonomous University of Guerrero, Lazaro Cárdenas S/N Col, Haciendita, Chilpancingo Guerrero, 39090, Mexico; E-Mail:
| | - Elizabeth J. Castaneda-Ortiz
- Genomics Sciences Program, Oncogenomics and Cancer Proteomics Laboratory, Autonomous University of Mexico City, Avenue San Lorenzo 290, 03100, Mexico; E-Mail:
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Noto JM, Peek RM. The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis. Front Cell Infect Microbiol 2012; 1:21. [PMID: 22919587 PMCID: PMC3417373 DOI: 10.3389/fcimb.2011.00021] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 12/12/2011] [Indexed: 12/13/2022] Open
Abstract
Gastric carcinogenesis is a multistep process orchestrated by aberrancies in the genetic and epigenetic regulation of oncogenes and tumor suppressor genes. Chronic infection with Helicobacter pylori is the strongest known risk factor for the development of gastric cancer. H. pylori expresses a spectrum of virulence factors that dysregulate host intracellular signaling pathways that lower the threshold for neoplastic transformation. In addition to bacterial determinants, numerous host and environmental factors increase the risk of gastric carcinogenesis. Recent discoveries have shed new light on the involvement of microRNAs (miRNAs) in gastric carcinogenesis. miRNAs represent an abundant class of small, non-coding RNAs involved in global post-transcriptional regulation and, consequently, play an integral role at multiple steps in carcinogenesis, including cell cycle progression, proliferation, apoptosis, invasion, and metastasis. Expression levels of miRNAs are frequently altered in malignancies, where they function as either oncogenic miRNAs or tumor suppressor miRNAs. This review focuses on miRNAs dysregulated by H. pylori and potential etiologic roles they play in H. pylori-mediated gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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