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Chen W, Wang W, Zhao Z, Wen Z, Li Y, Ge Z, Lai Y, Ni L. A three miRNAs panel in paraffin tissue serves as tool for predicting prognosis of renal cell carcinoma. Front Oncol 2024; 14:1391844. [PMID: 38720802 PMCID: PMC11076680 DOI: 10.3389/fonc.2024.1391844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/04/2024] [Indexed: 05/12/2024] Open
Abstract
Background Renal cell carcinoma (RCC) stands as the most prevalent form of urogenital cancer. However, there is currently no universally accepted method for predicting the prognosis of RCC. MiRNA holds great potential as a prognostic biomarker for RCC. Methods A total of 100 cases with complete paraffin specimens and over 5-year follow-up data meeting the requirements were collected. Utilizing the clinical information and follow-up data of the specimens, an information model was developed. The expression levels of eight microRNAs were identified using RT-qPCR. Finally, determine and analyze the clinical application value of these microRNAs as prognostic markers for RCC. Results Significant differences were observed in the expression of two types of miRNAs (miR-378a-5p, miR-23a-5p) in RCC tissue, and three types of miRNAs (miR-378a-5p, miR-642a-5p, miR-23a-5p) were found to be linked to the prognosis of RCC. Establish biomarker combinations of miR-378a-5p, miR-642a-5p, and miR-23a-5p to evaluate RCC prognosis. Conclusion The combination of three microRNA groups (miR-378a-5p, miR-642a-5p, and miR-23a-5p) identified in paraffin section specimens of RCC in this study holds significant potential as biomarkers for assessing RCC prognosis.
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Affiliation(s)
- Wenkang Chen
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Wuping Wang
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shenzhen University Medical College, Shenzhen, Guangdong, China
| | - Zhengping Zhao
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Zhenyu Wen
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Yingqi Li
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shenzhen University Medical College, Shenzhen, Guangdong, China
| | - Zhenjian Ge
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Yongqing Lai
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Liangchao Ni
- Guangdong and Shenzhen Key Laboratory of Reproductive Medicine and Genetics, Department of Urology, Peking University Shenzhen Hospital, Shenzhen, China
- Shantou University Medical College, Shantou, Guangdong, China
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Liu H, Wen J, Tian X, Li T, Zhao J, Cheng J, Huang L, Zhao Y, Cao Q, Jiang J. miR-125a-3p regulates the expression of FSTL1, a pro-inflammatory factor, during adipogenic differentiation, and inhibits adipogenesis in mice. FASEB J 2023; 37:e23146. [PMID: 37584664 DOI: 10.1096/fj.202300851r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/28/2023] [Accepted: 08/03/2023] [Indexed: 08/17/2023]
Abstract
Adipogenesis is tightly regulated by various factors, including genes and microRNAs. Excessive fat deposition is the key feature of obesity, which is a low-grade chronic inflammatory disease. Follistatin-like 1 (FSTL1) has been reported to be an important mediator involved in various inflammatory diseases. However, the underlying mechanism of FSTL1 in preadipocyte differentiation and inflammatory response is still unclear. The current study was designed to explore the biological function and potential mechanism of FSTL1 in mouse subcutaneous preadipocyte differentiation. We found that FSTL1 was highly expressed in the early stage of differentiation and subsequently decreased sharply, suggesting that FSTL1 played a possible role in adipogenesis. Meanwhile, the gain- and loss-of-function assays showed that FSTL1 was not only involved in the inflammatory response by inducing the expression of pro-inflammatory factors IL-1β and CCL2 but also significantly attenuated preadipocyte differentiation, as evidenced by the reduction of lipid accumulation and the levels of adipogenic genes, including PPARγ and FABP4. In addition, the target gene prediction and luciferase reporter assay validated that miR-125a-3p targeted the 3' UTR region of FSTL1. These results demonstrated that miR-125a-3p negatively regulated the expression of FSTL1 at the mRNA and protein levels. Furthermore, overexpressing miR-125a-3p in preadipocytes dramatically accelerated adipogenic differentiation and downregulated the levels of IL-1β and CCL2, which were in accordance with the knockdown of FSTL1. On the contrary, treatment with miR-125a-3p inhibitors attenuated adipogenesis but induced the expression of inflammatory genes. In summary, this study suggests a positive function of FSTL1 in adipocyte-induced inflammation and negatively regulates preadipocyte differentiation. Further studies demonstrated that miR-125a-3p could reverse the effect by targeting FSTL1, which might provide a better understanding of treating obesity-related inflammatory diseases.
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Affiliation(s)
- Haifeng Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Jie Wen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xue Tian
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Tong Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Ju Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Jingjing Cheng
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Lishi Huang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Ye Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Quanquan Cao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Jun Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
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Mari V, Angerilli V, Munari G, Scarpa M, Bao QR, Pucciarelli S, Fassan M, Spolverato G. Molecular Determinants of Peritoneal Dissemination in Gastric Adenocarcinoma. Dig Dis 2022; 41:49-65. [PMID: 35940137 DOI: 10.1159/000526333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Peritoneal dissemination represents a poor prognostic indicator in gastric cancer. Despite a comprehensive molecular characterization of this disease, no peritoneal dissemination-specific signature has been identified, limiting the tailoring of the surgical and oncological treatments. In this review, we outline the available literature focusing on the role of the different molecular pathways involved in the acquisition of peritoneal metastatic dissemination. SUMMARY According to our results, several molecular determinants are associated with peritoneal carcinomatosis and are involved in several cellular and molecular carcinogenetic processes. However, a comprehensive understanding of the complex molecular landscape of gastric carcinosis is still lacking. KEY MESSAGES More efforts should be made toward the integration of molecular and histologic data to perform a risk prediction assessment of peritoneal dissemination based on molecular profiling and histological evaluation.
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Affiliation(s)
- Valentina Mari
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giada Munari
- Veneto Institute of Oncology (I.O.V. IRCSS), Padua, Italy
| | - Marco Scarpa
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Quoc Riccardo Bao
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Salvatore Pucciarelli
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (I.O.V. IRCSS), Padua, Italy
| | - Gaya Spolverato
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
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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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5
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Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL. Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer. Free Radic Biol Med 2021; 170:150-178. [PMID: 33450375 PMCID: PMC8217091 DOI: 10.1016/j.freeradbiomed.2020.12.452] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023]
Abstract
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
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Affiliation(s)
- Danchen Wu
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Asish Dasgupta
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Austin D Read
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Rachel E T Bentley
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Mehras Motamed
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Ruaa Al-Qazazi
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Jeffrey D Mewburn
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Elahe Alizadeh
- Queen's Cardiopulmonary Unit (QCPU), Department of Medicine, Queen's University, 116 Barrie Street, Kingston, ON, K7L 3J9, Canada
| | - Lian Tian
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Stephen L Archer
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
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Razavi ZS, Asgarpour K, Mahjoubin-Tehran M, Rasouli S, Khan H, Shahrzad MK, Hamblin MR, Mirzaei H. Angiogenesis-related non-coding RNAs and gastrointestinal cancer. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:220-241. [PMID: 34095461 PMCID: PMC8141508 DOI: 10.1016/j.omto.2021.04.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal (GI) cancers are among the main reasons for cancer death globally. The deadliest types of GI cancer include colon, stomach, and liver cancers. Multiple lines of evidence have shown that angiogenesis has a key role in the growth and metastasis of all GI tumors. Abnormal angiogenesis also has a critical role in many non-malignant diseases. Therefore, angiogenesis is considered to be an important target for improved cancer treatment. Despite much research, the mechanisms governing angiogenesis are not completely understood. Recently, it has been shown that angiogenesis-related non-coding RNAs (ncRNAs) could affect the development of angiogenesis in cancer cells and tumors. The broad family of ncRNAs, which include long non-coding RNAs, microRNAs, and circular RNAs, are related to the development, promotion, and metastasis of GI cancers, especially in angiogenesis. This review discusses the role of ncRNAs in mediating angiogenesis in various types of GI cancers and looks forward to the introduction of mimetics and antagonists as possible therapeutic agents.
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Affiliation(s)
| | - Kasra Asgarpour
- Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Susan Rasouli
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Mohammad Karim Shahrzad
- Department of Internal Medicine and Endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Chen D, Su H, Li Y, Wu X, Li Y, Wei C, Shi D, Gao Y, Zhou Q, Wang Q, Jin X, Xie C. miR-20b and miR-125a promote tumorigenesis in radioresistant esophageal carcinoma cells. Aging (Albany NY) 2021; 13:9566-9581. [PMID: 33714953 PMCID: PMC8064182 DOI: 10.18632/aging.202690] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022]
Abstract
Radiation therapy is an effective method in the management of esophageal cancer. MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. However, the roles of specific miRNAs in radioresistant esophageal cancer remain to be investigated. In present study, the relative expression level of miR-20b-5p and miR-125a-5p were evaluated by quantitative Real-time polymerase chain reaction. Cell counting Kit-8 assay, wound-healing assay, transwell assay were used to assess cell proliferation, cell migration and cell invasion. TUNEL and Annexin V-FITC assays were applied to evaluate cell apoptosis. Dual-luciferase reporter gene assay was conducted to identify direct targets of miRNAs. The protein expression level was assessed by Western blot. The results indicated that miR-20b-5p was increased in radioresistant KYSE-150R cells compared with KYSE-150 cells, whereas miR-125a-5p was downregulated. MiR-20b-5p upregulation promoted cell proliferation, migration, invasion, and the EMT process, and decreased apoptosis by negatively regulating PTEN. MiR-125a-5p inhibited cell proliferation, migration, invasion, the EMT process and it induced apoptosis by negatively regulating IL6R. These data indicate that miR-20b-5p and miR-125a-5p promote tumorigenesis in radioresistant KYSE-150R cells and have the potential to be used as novel therapeutic targets for the treatment of esophageal cancer.
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Affiliation(s)
- Didi Chen
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huafang Su
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yunhao Li
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xinyi Wu
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yifei Li
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chaoyi Wei
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Deli Shi
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ya Gao
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qingyu Zhou
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiongqiong Wang
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiance Jin
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Congying Xie
- Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Ninio-Many L, Hikri E, Burg-Golani T, Stemmer SM, Shalgi R, Ben-Aharon I. miR-125a Induces HER2 Expression and Sensitivity to Trastuzumab in Triple-Negative Breast Cancer Lines. Front Oncol 2020; 10:191. [PMID: 32185126 PMCID: PMC7058585 DOI: 10.3389/fonc.2020.00191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 02/04/2020] [Indexed: 11/13/2022] Open
Abstract
The EGFR/HER2 signaling network is an effective therapeutic target for HER2-positive cancers, which are known for their aggressive biological course. Evidence indicates that the EGFR/HER2 network plays a role in the aggressive basal-like subtype as well. Here, we studied the potential role of miR-125a-3p as a modulator of the EGFR/HER2 pathway in basal-like breast cancer. Over-expression of miR-125a-3p reduced the migratory capability of MDA-MB-231 cells and led to an increase in the expression of ErbB2 transcript and protein. The induced ErbB2 responded to trastuzumab and underwent internalization and subsequent intra-lysosomal degradation. Trastuzumab treatment further reduced the migratory capability and induced the apoptosis of the cells. An in-vivo mouse model, which supported the in-vitro findings, showed a synergistic effect for miR-125a-3p and trastuzumab. Trastuzumab-treated miR-125a-3p-induced tumors were significantly smaller than control induced tumors. Our findings indicate that, in the basal-like subtype of breast cancer, miR-125a-3p may act as a tumor suppressor. miR-125a-3p induces an increase in the expression of ErbB2 that may render the cells suitable for treatment with anti-HER2 therapies.
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Affiliation(s)
- Lihi Ninio-Many
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Elad Hikri
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Tamar Burg-Golani
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Salomon M Stemmer
- Davidoff Center, Rabin Medical Center, Institute of Oncology, Petah-Tiqva, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Ruth Shalgi
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
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9
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Liu LZ, Wang M, Xin Q, Wang B, Chen GG, Li MY. The permissive role of TCTP in PM 2.5/NNK-induced epithelial-mesenchymal transition in lung cells. J Transl Med 2020; 18:66. [PMID: 32046740 PMCID: PMC7011287 DOI: 10.1186/s12967-020-02256-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/01/2020] [Indexed: 12/28/2022] Open
Abstract
Background Translationally controlled tumor protein (TCTP) is linked to lung cancer. However, upon lung cancer carcinogens stimulation, there were no reports on the relationship between TCTP and lung cell carcinogenic epithelial–mesenchymal transition (EMT). This study was designed to investigate the molecular mechanism of regulation of TCTP expression and its role in lung carcinogens-induced EMT. Methods To study the role of TCTP in lung carcinogens [particulate matter 2.5 (PM2.5) or 4-methylnitrosamino-l-3-pyridyl-butanone (NNK)]-induced EMT, PM2.5/NNK-treated lung epithelial and non-small cell lung cancer (NSCLC) cells were tested. Cell derived xenografts, human lung cancer samples and online survival analysis were used to confirm the results. MassArray assay, Real-time PCR and Reporter assays were performed to elucidate the mechanism of regulation of TCTP expression. All statistical analyses were performed using GraphPad Prism version 6.0 or SPSS version 20.0. Results Translationally controlled tumor protein and vimentin expression were up-regulated in PM2.5/NNK-treated lung cells and orthotopic implantation tumors. TCTP expression was positively correlated with vimentin in human NSCLC samples. Patients with high expression of TCTP displayed reduced overall and disease-free survival. TCTP overexpression could increase vimentin expression and promote cell metastasis. Furthermore, PM2.5/NNK stimulation brought a synergistic effect on EMT in TCTP-transfected cells. TCTP knockdown blocked PM2.5/NNK carcinogenic effect. Mechanically, PM2.5/NNK-induced TCTP expression was regulated by one microRNA, namely miR-125a-3p, but not by methylation on TCTP gene promoter. The level of TCTP was regulated by its specific microRNA during the process of PM2.5/NNK stimulation, which in turn enhanced vimentin expression and played a permissive role in carcinogenic EMT. Conclusions Our results provided new insights into the mechanisms of TCTP regulatory expression in lung carcinogens-induced EMT. TCTP and miR-125a-3p might act as potential prognostic biomarkers and therapeutic targets for NSCLC.
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Affiliation(s)
- Li-Zhong Liu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Physiology, School of Medicine, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China.
| | - Menghuan Wang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Physiology, School of Medicine, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Qihang Xin
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Physiology, School of Medicine, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Bowen Wang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Physiology, School of Medicine, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - George G Chen
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
| | - Ming-Yue Li
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong. .,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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10
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Liu Y, Wei G, Ma Q, Han Y. Knockdown of long noncoding RNA TP73-AS1 suppresses the malignant progression of breast cancer cells in vitro through targeting miRNA-125a-3p/metadherin axis. Thorac Cancer 2020; 11:394-407. [PMID: 31901156 PMCID: PMC6996984 DOI: 10.1111/1759-7714.13283] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND TP73 antisense RNA 1 (TP73-AS1) is a long noncoding RNA which has been shown to be involved in the progression of multiple malignant tumors. Previous studies have demonstrated the oncogenic role of TP73-AS1 in breast cancer. However, its molecular mechanism remains largely unknown in breast tumorigenesis. METHODS Expression of TP63-AS1, miRNA-125a-3p (miR-125a) and metadherin (MTDH) was detected by real-time quantitative PCR and western blotting. The malignancy was evaluated by cell counting kit 8 (CCK-8), transwell assays, flow cytometry and western blotting. The target binding was confirmed by dual luciferase reporter assay. Xenograft tumor model was performed to detect tumor growth in vivo. RESULTS Expression of TP73-AS1 was higher in breast cancer tissues and cell lines. Biologically, its knockdown could promote cell apoptosis rate, and inhibit proliferative capacity, migration and invasion ability in HCC-70 and MB231 cells, accompanied with higher cleaved caspase 3 level and lower Ki67, N-cadherin and Vimentin level. Moreover, TP73-AS1 downregulation restrained the tumor growth of HCC-70 cells in vivo. Mechanically, TP73-AS1 functioned as a molecular "sponge" for miR-125a to modulate MTDH, a downstream target of miR-125a. Intriguingly, both miR-125a overexpression and MTDH silencing exerted a tumor-suppressive effect in the malignant progression of HCC-70 and MB231 cells, which was counteracted by TP73-AS1 upregulation and miR-125a downregulation, respectively. CONCLUSION Knockdown of TP73-AS1 inhibited cell proliferation, migration and invasion, but facilitated apoptosis in breast cancer cells in vitro through targeting miR-125a and upregulating MTDH, suggesting a novel TP73-AS1/miR-125a/MTDH pathway in the malignant progression of breast cancer.
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Affiliation(s)
- Yuxiong Liu
- Department of General SurgeryChangji Huizu People's Hospital of XinjiangChangjiChina
| | - Guangqing Wei
- Department of General SurgeryHutubi People's Hospital of XinjiangChangjiChina
| | - Qian Ma
- Department of General SurgeryChangji Huizu People's Hospital of XinjiangChangjiChina
| | - Yanyan Han
- Department of Otolaryngology Head and Neck SurgeryXinjiang Urumqi Eye and ENT HospitalUrumqiChina
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11
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Wang J, Zheng Y, Bai B, Song Y, Zheng K, Xiao J, Liang Y, Bao L, Zhou Q, Ji L, Feng X. MicroRNA-125a-3p participates in odontoblastic differentiation of dental pulp stem cells by targeting Fyn. Cytotechnology 2020; 72:69-79. [PMID: 31953701 DOI: 10.1007/s10616-019-00358-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 11/23/2019] [Indexed: 12/30/2022] Open
Abstract
Fyn is a member of the protein tyrosine kinase family and its overexpression is associated with various types of inflammation. MicroRNAs can regulate the expression of target genes and play an important role in varied physiological and pathological processes. Based on the important role of Fyn and microRNA-125a-3p (miR-125a-3p) in inflammation, and combined with the bioinformatics studies, we performed in this study and chose miR-125a-3p as the focus of our research. During the progression of inflammation, we found that the expression of miR-125a-3p was decreased while the expression of Fyn was up-regulated. Fyn formed a complex with Neuropilin-1, which inhibited odontoblastic differentiation and expanded inflammatory responses through nuclear factor-κB signal pathways in dental pulp stem cells (DPSCs). These findings suggested that miR-125a-3p plays an important role in odontoblastic differentiation of DPSCs by targeting Fyn, implying its therapeutic potential in dental caries.
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Affiliation(s)
- Jihua Wang
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Ya Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.,Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Bingbing Bai
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Yihua Song
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Ke Zheng
- Department of Stomatology, Wuxi No. 2 People Hospital, Wuxi, 214000, China
| | - Jinwen Xiao
- Department of Stomatology, People's Hospital of Haimen, Nantong, China
| | - Yi Liang
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Liuliu Bao
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Qiao Zhou
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Lujun Ji
- Department of Stomatology, Tongzhou People's Hospital, Taizhou, 225300, China.
| | - Xingmei Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
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12
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Yang M, Tang X, Wang Z, Wu X, Tang D, Wang D. miR-125 inhibits colorectal cancer proliferation and invasion by targeting TAZ. Biosci Rep 2019; 39:BSR20190193. [PMID: 31782506 PMCID: PMC6911154 DOI: 10.1042/bsr20190193] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 11/06/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor worldwide and is a serious threat to human health. MicroRNAs (miRNAs) play a key role in oncogenesis and cancer progression. MiRNA-125 (miR-125) is an important miRNA that is dysregulated in several kinds of cancers. Thus, we investigated the expression and effects of miR-125 and Transcriptional co-activator with PDZ-binding motif (TAZ) for a better understanding of the underlying mechanism of tumor progression in CRC, which may provide an emerging biomarker for diagnosis and treatment of CRC. We measured the expression levels of miR-125 in CRC tissues, adjacent tissues, and cell lines (e.g. HCT116, SW480, FHC) by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of miR-125 on proliferation and invasion in CRC cells was detected by Cell Counting Kit-8 (CCK-8), clone formation assay, and transwell assay. Western blotting and qRT-PCR were used to investigate the expression of TAZ after knocking down miR-125 in HCT116 cells or overexpressing miR-125 in SW480 cells. MiR-125 was significantly down-regulated in CRC compared with pericarcinomatous tissue from 18 patients. An miR-125 inhibitor promoted CRC cell proliferation and invasion, while miR-125 mimic had the opposite effect. Moreover, we found that TAZ was an miR-125 target and the siRNA knockdown of TAZ could reverse the effect of the miR-125 inhibitor on proliferation and invasion in HCT116 cells. The present study shows that miR-125 suppresses CRC proliferation and invasion by targeting TAZ.
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Affiliation(s)
- Meiyuan Yang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Renmin Road No.139, Changsha 410001, China
| | - Xiaoli Tang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Renmin Road No.139, Changsha 410001, China
| | - Zheng Wang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
| | - Xiaoqing Wu
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
| | - Dong Tang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
- Department of General Surgery, Medical College, Yangzhou University, Northern Jiangsu Province Hospital, General Surgery Institute of Yangzhou University, Nantong Road No.98, Yangzhou 225001, China
| | - Daorong Wang
- Department of General Surgery, Clinical Medical College of Yangzhou University, Huaihai Road No.7, Yangzhou 225001, China
- Department of General Surgery, Medical College, Yangzhou University, Northern Jiangsu Province Hospital, General Surgery Institute of Yangzhou University, Nantong Road No.98, Yangzhou 225001, China
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13
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Li G, Ao S, Hou J, Lyu G. Low expression of miR-125a-5p is associated with poor prognosis in patients with gastric cancer. Oncol Lett 2019; 18:1483-1490. [PMID: 31423214 PMCID: PMC6607383 DOI: 10.3892/ol.2019.10423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 04/16/2019] [Indexed: 12/19/2022] Open
Abstract
microRNAs (miRs) serve critical roles in tumor progression. Low expression of miR-125a in gastric carcinoma (GC) may promote tumor development. In the present study, low expression of miR-125a was confirmed in cancer tissues using The Cancer Genome Atlas database. Additionally, the expression and clinical significance of miR-125a-5p was investigated using reverse transcription-quantitative PCR in 150 cases of GC. The results of the present study demonstrated that the level of miR-125a-5p expression was decreased in GC biopsies compared with that in matched adjacent normal tissues. Low expression of miR-125a-5p was associated with increased tumor diameter, high Ki67 expression and poor overall survival of patients with GC. Multivariate survival analysis demonstrated that low miR-125a-5p expression may be used as an independent prognostic factor for patients with GC. However, no effects on the cell viability in a Cell Counting kit-8 assay, and cell migration and invasion in Transwell assays were detected in response to treatment using miR-125a-5p mimics or inhibitors in vitro. Therefore, the results of the present study provide evidence that low expression of miR-125a-5p may be associated with a poor prognosis, suggesting its value as a tumor biomarker for patients with GC.
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Affiliation(s)
- Guan Li
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Sheng Ao
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Jianing Hou
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Guoqing Lyu
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
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14
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HULC functions as an oncogene in ovarian carcinoma cells by negatively modulating miR-125a-3p. J Physiol Biochem 2019; 75:163-171. [PMID: 30863948 DOI: 10.1007/s13105-019-00669-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 02/19/2019] [Indexed: 01/17/2023]
Abstract
The aberrant expression of highly upregulated in liver cancer (HULC) has been reported to participate in ovarian cancer development. A recent research has revealed that HULC-modulated microRNAs (miRNAs) in tumorigenesis. To confirm the functions of HULC on tumorigenesis of ovarian, we explored the effects of HULC expression on ovarian cancer cell development, as well as the underlying mechanism. We transfected SKOV3 cells with pEX-HULC, sh-HULC, and miR-125a-3p mimic as well as their corresponding negative controls (pEX-3, sh-NC, and NC) to alter the expression of HULC and miR-125a-3p, which were analyzed by quantitative reverse transcription PCR (qRT-PCR). Expression of proteins associated with cell cycle, apoptosis, and signaling pathways was determined by Western blot assay. The proliferation, apoptosis, migration, and invasion were explored by bromodeoxyuridine (BrdU) incorporation assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) method, and transwell migration and invasion assays, respectively. HULC overexpression promoted proliferation, migration, and invasion, while inhibited apoptosis of SKOV3 cells. In addition, HULC negatively regulated the expression of miR-125a-3p. Besides, miR-125a-3p mimic reversed the effects of HULC on proliferation, migration, and invasion as well as apoptosis of SKOV3 cells. Moreover, we found that HULC enhanced phosphorylated expression of regulatory factors in phosphatidylinositol 3 kinase/protein kinase B/mammalian targets of rapamycin (PI3K/AKT/mTOR) signaling pathway by downregulating expression of miR-125a-3p. Overexpression of HULC promoted ovarian carcinoma development by activating PI3K/AKT/mTOR signaling pathway via downregulating miR-125a-3p.
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15
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Huang JF, Jiang HY, Cai H, Liu Y, Zhu YQ, Lin SS, Hu TT, Wang TT, Yang WJ, Xiao B, Sun SH, Ma LY, Yin HR, Wang F. Genome-wide screening identifies oncofetal lncRNA Ptn-dt promoting the proliferation of hepatocellular carcinoma cells by regulating the Ptn receptor. Oncogene 2019; 38:3428-3445. [PMID: 30643194 DOI: 10.1038/s41388-018-0643-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 10/04/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023]
Abstract
Oncofetal genes are genes that express abundantly in both fetal and tumor tissues yet downregulated or undetected in adult tissues, and can be used as tumor markers for cancer diagnosis and treatment. Meanwhile, long noncoding RNAs (lncRNAs) are known to play crucial roles in the pathogenesis of hepatocellular carcinoma (HCC), including tumor growth, proliferation, metastasis, invasion, and recurrence. We performed a genome-wide screening using microarrays to detect the lncRNA expression profiles in fetal livers, adult livers, and liver cancer tissues from mice to identify oncofetal lncRNAs in HCC. From the microarray data analysis, we identified lncRNA Ptn-dt as a possible oncofetal gene. Both in vitro and in vivo experiments results confirmed that overexpression of Ptn-dt significantly promoted the proliferation of mouse HCC cells. RNA pulldown assay showed that Ptn-dt could interact with the HuR protein. Interestingly, miR-96 binds with HuR to maintain its stability as well. Overexpression of lncRNA Ptn-dt led to the downregulation of miR-96, which might be due to the interaction between Ptn-dt and HuR. Meanwhile, previous studies have reported that Ptn can promote tumor growth and vascular abnormalization via anaplastic lymphoma kinase (Alk) signaling. In our study, we found that overexpression of Ptn-dt could promote the expression of Alk through repressing miR-96 via interacting with HuR, thus enhancing the biologic function of Ptn. In summary, a new oncofetal lncRNA Ptn-dt is identified, and it can promote the proliferation of HCC cells by regulating the HuR/miR-96/Alk pathway and Ptn-Alk axis.
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Affiliation(s)
- Jin-Feng Huang
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China.,Department of Clinical Genetics, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Hong-Yue Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Hui Cai
- Department of General Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Yan Liu
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China
| | - Yi-Qing Zhu
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China
| | - Sha-Sha Lin
- Center of Reproductive Medicine, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Ting-Ting Hu
- Center of Reproductive Medicine, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Tian-Tian Wang
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China.,Department of Clinical Genetics, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Wen-Jun Yang
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China
| | - Bang Xiao
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China
| | - Shu-Han Sun
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China.,Department of Clinical Genetics, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China
| | - Li-Ye Ma
- Department of General Surgery, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.
| | - Hui-Rong Yin
- Center of Reproductive Medicine, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.
| | - Fang Wang
- Department of Medical Genetics, Second Military Medical University, 200433, Shanghai, China. .,Department of Clinical Genetics, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.
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16
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Li X, Chen B, Chi D, Zhang Y, Jiang W. lncRNA CASC9 regulates cell migration and invasion in hemangioma endothelial cells by targeting miR-125a-3p/Nrg1. Onco Targets Ther 2019; 12:423-432. [PMID: 30662268 PMCID: PMC6327889 DOI: 10.2147/ott.s181914] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Despite being one of the most common benign tumors, the prevalence and pathogenesis of hemangiomas (HAs) are poorly understood. We aimed to identify the biological role of the long non-coding RNA (lncRNA) CASC9 in the HA-derived endothelial cell (HDECs) phenotype as well as elucidate the mechanism involved. Methods The expression of CASC9 was identified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). the effect of CASC9 on cell proliferation, migration and invasion of HDECs were examined by CCK8, wound healing, and transwell assay, respectively. Bioinformatics analysis and a luciferase reporter assay were utilized to investigated the mechanisms involved. The in vivo tumorigenesis capability of CASC9 on HA was also evaluated. Results The expression of CASC9 was significantly elevated in HA tissue compared to normal tissue. Down-regulation of CASC9 inhibited proliferation, migration, and invasion of HDECs. The translation of cyclinD1, N-cadherin, Twist, and MMP2 was also decreased by CASC9 knockdown treatment. Furthermore, CASC9 over-expression exerted the opposite effect of proliferation, migration, and invasion of HDECs. We also found that CASC9 interacts with miR-125a-3p/Nrg1 to regulate cellular functions. Interestingly, miR-125a-3p can reverse the effect of CASC9 on proliferation, migration, and invasion of HDECs. Together, the clinical data showed that CASC9 expression is negatively correlated with miR-125a-3p expression and positively correlated with Nrg1 expression. CASC9 also exerted anti-tumorigenesis capability in vivo. Conclusion Our study indicates that CASC9 accelerates cell growth and invasion of HDECs and provides new insights for the diagnosis and molecular therapy of HA.
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Affiliation(s)
- Xianwei Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China,
| | - Bo Chen
- Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China,
| | - Decai Chi
- Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China,
| | - Yingnan Zhang
- Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China,
| | - Weiliang Jiang
- Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, People's Republic of China,
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17
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Yang X, Qiu J, Kang H, Wang Y, Qian J. miR-125a-5p suppresses colorectal cancer progression by targeting VEGFA. Cancer Manag Res 2018; 10:5839-5853. [PMID: 30510452 PMCID: PMC6248379 DOI: 10.2147/cmar.s161990] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background MiR-125a-5p has been reported to be involved in the development and progression of various cancers. However, the biological function and underlying mechanisms in colorectal cancer(CRC) still remain unclear. Here, we explored the potential biological roles of miR-125a-5p in CRC. Methods The expression of miR-125a-5p was detected using quantitative real-time PCR (qRT-PCR), biological functions of miR-125a-5p were assessed by cell counting kit-8, wound-healing, transwell invasion, and human umbilical vein endothelial cell (HUVEC) tube formation assays in vitro and animal experiments in vivo. Results We found that miR-125a-5p was downregulated in CRC tissues and cell lines, it inhibited CRC cell proliferation, migration, and invasion and reduced the ability of HUVECs to form tubes. Moreover, we verifed that miR-125a-5p suppressed CRC growth and metastasis in vivo. Additionally, we showed that VEGFA, a direct target gene of miR-125a-5p, could reverse the inhibitory effect caused by miR-125a-5p overexpression. Conclusion miR-125a-5p might serve as a tumor suppressor in CRC and could be regarded as a potential therapeutic candidate for CRC.
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Affiliation(s)
- Xuehua Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China,
| | - Jianwei Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China,
| | - Haifeng Kang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China,
| | - Yaming Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China,
| | - Junbo Qian
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China,
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18
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Yuan HL, Wang T, Zhang KH. MicroRNAs as potential biomarkers for diagnosis, therapy and prognosis of gastric cancer. Onco Targets Ther 2018; 11:3891-3900. [PMID: 30013369 PMCID: PMC6039071 DOI: 10.2147/ott.s156921] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite the widespread use of endoscopy and conventional tumor biomarkers, gastric cancer (GC) remains one of the most frequent causes of cancer-related deaths worldwide due to its late diagnosis and poor response to treatment. Valuable and practical biomarkers are urgently needed to screen patients with a high risk of GC that can complement endoscopic diagnosis. Such biomarkers will enable the efficient prediction of therapeutic response and prognosis of GC patients and favor the establishment of an effective treatment strategy for each and every patient. MicroRNAs (miRNAs) are a class of small non-coding RNA sequences that play important roles in modulating key biological processes by regulating the expression of target genes. Expectedly, miRNAs are abnormally expressed within the tumor tissue and in associated biological fluids of GC patients including their blood, gastric juice, and urine. Accumulating evidence indicates that miRNAs are potential biomarkers with multiple diagnostic functions for GC. Here, we review recent advances and challenges in using miRNAs, particularly biofluid miRNAs, as GC biomarkers with potential clinical applications including diagnosing, clinically staging, and predicting malignant behaviors, therapy response, recurrence after surgery and survival time.
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Affiliation(s)
- Hai-Liang Yuan
- Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People's Republic of China,
| | - Ting Wang
- Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People's Republic of China,
| | - Kun-He Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, People's Republic of China,
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19
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Evert J, Pathak S, Sun XF, Zhang H. A Study on Effect of Oxaliplatin in MicroRNA Expression in Human Colon Cancer. J Cancer 2018; 9:2046-2053. [PMID: 29896290 PMCID: PMC5995942 DOI: 10.7150/jca.24474] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/14/2018] [Indexed: 12/26/2022] Open
Abstract
Colorectal cancer is a commonly diagnosed malignancy and also the major cause of death worldwide. Chemotherapy is the primary therapy for advanced colorectal cancer. Although oxaliplatin has potential effect in colorectal cancer therapy, the molecular mechanisms involved in its cytotoxic effects are not well elucidated. This study outlines the regulatory effects of oxaliplatin on miRNAs expression in colon cancer cells and correlates it with the changing microRNA expression with p53 and p73 expression status in cells. HCT116p53+/+ and HCT116p53-/- cells were exposed to oxaliplatin, and the cellular viability was determined by XTT. p73 was knocked down using siRNA and the tumor cells were then treated with oxaliplatin. The expression profile of 384 miRNAs was determined by TaqMan® human miRNA array and calculated by the ∆∆Ct method. Cellular viability was found to decrease after the treatment with oxaliplatin in a dose-dependent manner. The wild-type p53 cells were found to be more sensitive than the null-p53 derivatives. A selective set of miRNAs were either up-regulated or down-regulated in response to the oxaliplatin treatment with a presumable role of p53 and p73 proteins. The miRNAs expression is known to influence the pharmacodynamic mechanisms of oxaliplatin and these effects have been observed to be regulated by p53 and p73. Our results may therefore provide more evidence for identifying a suitable biomarker for the diagnosis of colon cancer.
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Affiliation(s)
- Jasmine Evert
- School of Medical Sciences, Örebro University, SE 70182 Örebro, Sweden
| | - Surajit Pathak
- Department of Oncology and Department of Clinical and Experimental Medicine, SE-581 83, Linköping University, Linköping, Sweden.,Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, India, 603 103
| | - Xiao-Feng Sun
- Department of Oncology and Department of Clinical and Experimental Medicine, SE-581 83, Linköping University, Linköping, Sweden
| | - Hong Zhang
- School of Medical Sciences, Örebro University, SE 70182 Örebro, Sweden
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20
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The upregulation of TMPRSS4, partly ascribed to the downregulation of miR‑125a‑5p, promotes the growth of human lung adenocarcinoma via the NF‑κB signaling pathway. Int J Oncol 2018; 53:148-158. [PMID: 29750426 PMCID: PMC5958727 DOI: 10.3892/ijo.2018.4396] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 04/20/2018] [Indexed: 12/13/2022] Open
Abstract
In this study, with the aid of microarray technology, transmembrane protease serine 4 (TMPRSS4), a novel member of the serine protease family, was found to be upregulated in the majority of lung adenocarcinoma (LUAD) tissues compared to normal lung tissues. Of note, the clinical significance of TMPRSS4 in LUAD has not yet been reported, at least to the best of our knowledge. Through immunohistochemistry assays, we found that TMPRSS4 was overexpressed in LUAD tissues and that the TMPRSS4 expression level was also proportionally associated with the AJCC clinical stage, T stage and pathological grade. Moreover, a high expression of TMPRSS4 was found to be associated with adverse outcomes and was a significant independent factors predicting a poor prognosis. To elucidate the possible mechanisms responsible for the overexpression of TMPRSS4, we examined at microRNAs (miRNAs or miRs), which are small non-coding RNAs commonly dysregulated in human malignancies and are known to promote carcinogenesis by interacting with other types of RNAs. By means of bioinformatics analysis, a miRNA potentially targeting TMPRSS4 mRNA, namely miR-125a-5p, was selected. Dual luciferase reporter gene assays were then performed to verify the interaction. The results of MTT assays and apoptotic assays revealed that miR-125a-5p significantly inhibited cell growth and enhanced apoptosis, and the silencing of TMPRSS4 had similar effects. Furthermore, we observed that either the overexpression of miR-125a-5p or the silencing of TMPRSS4 prevented the activation of the nuclear factor (NF)-κB signaling pathway. On the whole, our findings illustrate that TMPRSS4 may be a candidate oncogene and may thus serve as a prognostic biomarker for LUAD, and its overexpression may be partly ascribed to the downregulation of miR-125a-5p. The dysregulation of miR-125a-5p and TMPRSS4 affect the biological function of LUAD cells via the NF-κB signaling pathway. The miR-125a-5p/TMPRSS4/NF-κB axis may thus provide novel insight into the pathogenic mechanisms of LUAD and may be used in the development of novel treatment strategies for LUAD.
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21
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Pan L, Zhou L, Yin W, Bai J, Liu R. miR-125a induces apoptosis, metabolism disorder and migrationimpairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission. Int J Oncol 2018; 53:124-136. [PMID: 29749475 PMCID: PMC5958665 DOI: 10.3892/ijo.2018.4380] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 04/02/2018] [Indexed: 12/13/2022] Open
Abstract
Mitochondrial fission is important for the development and progression of pancreatic cancer (PC). However, little is known regarding its role in pancreatic cancer apoptosis, metabolism and migration. In the current study, the mechanism by which mitochondrial fission modifies the biological characteristics of PC was explored. MicroRNA-125a (miR-125a) had the ability to inhibit mitochondrial fission and contributed to cellular survival. Suppressed mitochondrial fission led to a reduction in mitochondrial debris, preserved the mitochondrial membrane potential, inhibited mitochondrial permeability transition pore opening, ablated cytochrome c leakage into the cytoplasm and reduced the pro-apoptotic protein contents, finally blocking mitochondria related apoptosis pathways. Furthermore, defective mitochondrial fission induced by miR-125a enhanced mitochondria-dependent energy metabolism by promoting activity of electron transport chain complexes. Furthermore, suppressed mitochondrial fission also contributed to PANC-1 cell migration by preserving the F-actin balance. Furthermore, mitofusin 2 (Mfn2), the key defender of mitochondrial fission, is involved in inhibition of miR125a-mediated mitochondrial fission. Low contents of miR-125a upregulated Mfn2 transcription and expression, leading to inactivation of mitochondrial fission. Ultimately, the current study determined that miR-125a and Mfn2 are regulated by hypoxia-inducible factor 1 (HIF1). Knockdown of HIF1 reversed miR-125a expression, and therefore, inhibited Mfn2 expression, leading to activation of mitochondrial fission. Collectively, the present study demonstrated mitochondrial fission as a tumor suppression process that is regulated by the HIF/miR-125a/Mfn2 pathways, acting to restrict PANC-1 cell survival, energy metabolism and migration, with potential implications for novel approaches for PC therapy.
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Affiliation(s)
- Lichao Pan
- The Second Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Lin Zhou
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Weijia Yin
- Department of Biochemistry, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jia Bai
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Rong Liu
- The Second Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
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22
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Complex Epigenetic Regulation of Chemotherapy Resistance and Biohlogy in Esophageal Squamous Cell Carcinoma via MicroRNAs. Int J Mol Sci 2018; 19:ijms19020499. [PMID: 29414899 PMCID: PMC5855721 DOI: 10.3390/ijms19020499] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 01/27/2018] [Accepted: 01/27/2018] [Indexed: 12/17/2022] Open
Abstract
Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. Results: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.006). Conclusion: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions.
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23
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Chen X, Cui Y, Xie X, Xing Y, Yuan Z, Wei Y. Functional role of miR-27b in the development of gastric cancer. Mol Med Rep 2018; 17:5081-5087. [PMID: 29393383 PMCID: PMC5865971 DOI: 10.3892/mmr.2018.8538] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 07/07/2017] [Indexed: 12/22/2022] Open
Abstract
Previous studies have demonstrated that microRNAs (miRNAs/miRs) act as tumor suppressors or oncogenes during multiple processes in cancer. It has been observed that miR-27b may act as a tumor-suppressor and was significantly downregulated in a number of types of cancer. However, the functions of miR-27b in gastric cancer (GC) remain unclear. The present study aimed to investigate the functional role of miR-27b in the progression of GC. The downregulation of miR-27b in human GC plasma was confirmed using miRNA microarray and reverse transcription-quantitative polymerase chain reaction analyses. The association between circulating miR-27b expression and clinicopathological features of GC was analyzed and the results demonstrated that the level of circulating miR-27b was significantly correlated with GC differentiation. Receiver operating characteristic curve analysis identified that the plasma level of miR-27b may be a potential biomarker for differentiating patients with GC from healthy controls. In order to investigate the effect of miR-27b on GC cell behavior, miR-27b was overexpressed using miR-27b mimics, and it was observed that miR-27b was able to inhibit cell proliferation and induce apoptosis in SGC7901 cells. Previous studies have demonstrated that vascular endothelial growth factor C (VEGFC) is a target of miR-27b, and the results of the present study were consistent with these reports. Taken together, the results of the present study indicated that miR-27b may act as a potential biomarker for differentiating patients with GC from healthy controls, and serve as a tumor suppressor in GC by targeting VEGFC.
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Affiliation(s)
- Xiaojie Chen
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yejia Cui
- Department of Clinical Laboratory, Dongguan Third People's Hospital, Dongguan, Guangdong 523326, P.R. China
| | - Xuhong Xie
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yanfen Xing
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Zhaohu Yuan
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yaming Wei
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
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24
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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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25
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Li H, Wang X, Wen C, Huo Z, Wang W, Zhan Q, Cheng D, Chen H, Deng X, Peng C, Shen B. Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia-induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer. Mol Cancer 2017; 16:169. [PMID: 29121972 PMCID: PMC5679488 DOI: 10.1186/s12943-017-0738-0] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 11/01/2017] [Indexed: 12/16/2022] Open
Abstract
Background Pancreatic cancer, one of the top two most fatal cancers, is characterized by a desmoplastic reaction that creates a dense microenvironment, promoting hypoxia and inducing the epithelial-to-mesenchymal transition (EMT) to facilitate invasion and metastasis. Recent evidence indicates that the long noncoding RNA NORAD may be a potential oncogenic gene and that this lncRNA is significantly upregulated during hypoxia. However, the overall biological role and clinical significance of NORAD remains largely unknown. Methods NORAD expression was measured in 33 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of NORAD on pancreatic cancer cells were studied by overexpression and knockdown in vitro. Insights into the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatics analyses and luciferase assays. In vivo, metastatic potential was identified using an orthotopic model of PDAC and quantified using bioluminescent signals. Alterations in RhoA expression and EMT levels were identified and verified by immunohistochemistry and Western blotting. Results NORAD is highly expressed in pancreatic cancer tissues and upregulated in hypoxic conditions. NORAD upregulation is correlated with shorter overall survival in pancreatic cancer patients. Furthermore, NORAD overexpression promoted the migration and invasion of pancreatic carcinoma cells, while NORAD depletion inhibited EMT and metastasis in vitro and in vivo. In particular, NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p, thereby promoting EMT. Conclusions Elevated expression of NORAD in pancreatic cancer tissues is linked to poor prognosis and may confer a malignant phenotype upon tumor cells. NORAD may function as a ceRNA to regulate the expression of the small GTP binding protein RhoA through competition for hsa-miR-125a-3p. This finding may contribute to a better understanding of the role played by lncRNAs in hypoxia-induced EMT and provide a potential novel diagnostic and therapeutic target for pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s12943-017-0738-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hongzhe Li
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xinjing Wang
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenlei Wen
- Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Huo
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Weishen Wang
- Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Zhan
- Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dongfeng Cheng
- Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Chen
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaxing Deng
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenghong Peng
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Baiyong Shen
- Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. .,Pancreatic Disease Centre, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. .,Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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26
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Sun F, Feng M, Guan W. Mechanisms of peritoneal dissemination in gastric cancer. Oncol Lett 2017; 14:6991-6998. [PMID: 29344127 DOI: 10.3892/ol.2017.7149] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/21/2017] [Indexed: 12/15/2022] Open
Abstract
Peritoneal dissemination is the most frequent metastatic pattern of gastric cancer, but the mechanisms underlying peritoneal dissemination are yet to be elucidated. Paget's 'seed and soil' hypothesis is recognized as the fundamental theory of metastasis. The 'seeding' theory proposes that the formation of peritoneal dissemination is a multistep process, including detachment from the primary tumour, transmigration and attachment to the distant peritoneum, invasion into subperitoneal tissue and proliferation with blood vascular neogenesis. In the present review, the progress of each step is discussed. Milky spots, as a lymphatic apparatus, are indicative of lymphatic orifices on the surface of the peritoneum. These stomata are open gates for peritoneal-free cancer cells to migrate into the submesothelial space. Therefore, milky spots provide suitable 'soil' for cancer cells to implant. Other theories have also been proposed to clarify the peritoneal dissemination process, including the transvessel metastasis theory, which suggests that the peritoneal metastasis of gastric cancer develops via a vascular network mediated by hypoxia inducible factor-1α.
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Affiliation(s)
- Feng Sun
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Min Feng
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
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27
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Lu G, Ma Y, Jia C, Yang H, Xie R, Luo P, Chai L, Cai H, Cai M, Lv Z, Cong X, Fu D. Reduced miR-125a levels associated with poor survival of patients with hepatocellular cancer. Oncol Lett 2017; 14:5952-5958. [PMID: 29113231 PMCID: PMC5661598 DOI: 10.3892/ol.2017.6902] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/15/2017] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) serve an important role in tumorigenesis and development. Although a low expression of miR-125a in hepatocellular carcinoma (HCC) has been reported, the clinical significance remains unknown. In the current study, the data of Gene Expression Omnibus datasets was analyzed and significantly low expression of miR-125a in HCC was verified. Furthermore, the expression and clinical significance of miR-125a was investigated in 27 normal liver and 98 HCC tissue samples using reverse transcription-quantitative polymerase chain reaction analysis. The results demonstrated that the level of miR-125a expression was lower in HCC biopsies compared with that in normal liver tissues. Survival analysis established that miR-125a expression was negatively associated with the prognosis of HCC. Multivariate survival analysis demonstrated that patients with HCC with lowmiR-125a and Ki67-positive expression have shorter overall, and disease-free survival times. Altogether, the results of the current study provide the first evidence that reducedmiR-125a expression is associated with HCC progression and poor prognosis in patients, suggesting that miR-125a may have potential prognostic value as a tumor biomarker for patients with HCC.
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Affiliation(s)
- Gaixia Lu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yushui Ma
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chengyou Jia
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Huiqiong Yang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Ruting Xie
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Pei Luo
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Li Chai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Haidong Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Mingxiang Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xianling Cong
- Tissue Bank, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Da Fu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.,Research Center of Clinical Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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28
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Emamdoost F, Khanahmad H, Ganjalikhani-hakemi M, Doosti A. The miR-125a-3p Inhibits TIM-3 Expression in AML Cell Line HL-60 In Vitro. Indian J Hematol Blood Transfus 2017; 33:342-347. [PMID: 28824235 PMCID: PMC5544632 DOI: 10.1007/s12288-016-0733-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 09/26/2016] [Indexed: 02/08/2023] Open
Abstract
Acute Myeloid Leukemia is a cancer of leukemic stem cells (LSCs) with a rapid progression. It is characterized by overproduction of immature myeloid cells in bone marrow which crowds out normal hematopoietic stem cells (HSC). TIM-3, an immune regulatory molecule, is an LSC specific surface marker in AML with high expression on these cells compared to HSCs. Studies have indicated that micro RNAs (miRNAs) may play an important role in either cancer progression or suppression. Based on bioinformatics assessments, we have predicted that miR-125a-3p could be a miRNA with high suppressive activity on TIM-3 expression. The purpose of this study was to investigate the inhibitory effect of miR-125a-3p on TIM-3 gene expression in an AML cell line, HL-60, in vitro. HL-60 cells were cultured in RPMI 1640 supplied with 10 % FBS. TIM-3 expression was induced on the cells using phorbol miristate acetate. The cells were transfected with miR-125-3p for 24 h and the gene and protein expression of TIM-3 were measured using q-RT-PCR and flow-cytometery methods, respectively. The results of this study showed that miR-125a-3p has a strong silencing effect on TIM-3 gene and protein expression on HL-60 cell line. Based to our results, miR125a-3p can strongly silence TIM-3 expression in AML cell line. Thus, our results have confirmed the bioinformatics prediction of suppressive effect of miR-125a-3p on TIM-3with Mirwalk and Target Scan softwares.
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Affiliation(s)
- Fatemeh Emamdoost
- Department of Genetics, Faculty of Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Hossein Khanahmad
- Department of Genetics, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Abbas Doosti
- Department of Genetics, Faculty of Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
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29
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Hou L, Luo P, Ma Y, Jia C, Yu F, Lv Z, Wu C, Fu D. MicroRNA-125a-3p downregulation correlates with tumorigenesis and poor prognosis in patients with non-small cell lung cancer. Oncol Lett 2017; 14:4441-4448. [PMID: 29085440 PMCID: PMC5649526 DOI: 10.3892/ol.2017.6809] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 12/20/2016] [Indexed: 11/05/2022] Open
Abstract
MicroRNA (miR)-125a-3p is derived from the 3'-end of pre-miR-125a, which is associated with several types of cancer, such as gastric and prostate cancer, and glioma. The aim of the present study was to identify the prognostic significance of miR-125a-3p expression levels in patients with NSCLC. The gene expression omnibus database was used to analyze miR-125a-3p expression in NSCLC in silico, and 148 NSCLC samples and 30 adjacent normal lung tissue specimens were analyzed for the expression of miR-125a-3p by qPCR. The results showed that the expression levels of miR-125a-3p in the adjacent normal tissues was higher than the expression level in the NSCLC tissues. There were several clinical parameters demonstrated to be associated with miR-125a-3p expression, such as lymph node metastasis, tumor node metastasis classification of malignant tumor stage and tumor diameter. Furthermore, high expression levels of miR-125a-3p with chemotherapy prolonged the overall survival rate and disease free survival rate compared with untreated patients with low expression of miR-125a-3p. Thus, miR-125a-3p is a significant prognostic biomarker for patients with NSCLC, from which a novel therapeutic strategy to combat NSCLC may be derived.
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Affiliation(s)
- Likun Hou
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China
| | - Pei Luo
- Veterinary Faculty, College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan 410128, P.R. China
| | - Yushui Ma
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chengyou Jia
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Fei Yu
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chunyan Wu
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China
| | - Da Fu
- Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.,Central Laboratory for Medical Research, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Zhang Y, Guan DH, Bi RX, Xie J, Yang CH, Jiang YH. Prognostic value of microRNAs in gastric cancer: a meta-analysis. Oncotarget 2017; 8:55489-55510. [PMID: 28903436 PMCID: PMC5589675 DOI: 10.18632/oncotarget.18590] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/08/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Previous articles have reported that expression levels of microRNAs (miRNAs) are associated with survival time of patients with gastric cancer (GC). A systematic review and meta-analysis was performed to study the outcome of it. DESIGN Meta-analysis. METHODS English studies estimating expression levels of miRNAs with any of survival curves in GC were identified up till March 19, 2017 through performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two authors independently. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS). RESULTS Sixty-nine relevant articles about 26 miRNAs with 6148 patients were ultimately included. GC patients with high expression of miR-20b (HR=2.38, 95%CI=1.16-4.87), 21 (HR=1.77, 95%CI=1.01-3.08), 106b (HR=1.84, 95%CI=1.15-2.94), 196a (HR=2.66, 95%CI=1.94-3.63), 196b (HR=1.67, 95%CI=1.38-2.02), 214 (HR=1.84, 95%CI=1.27-2.67) or low expression of miR-125a (HR=2.06, 95%CI=1.26-3.37), 137 (HR=3.21, 95%CI=1.68-6.13), 141 (HR=2.47, 95%CI=1.34-4.56), 145 (HR=1.62, 95%CI=1.07-2.46), 146a (HR=2.60, 95%CI=1.63-4.13), 206 (HR=2.85, 95%CI=1.73-4.70), 218 (HR=2.61, 95%CI=1.74-3.92), 451 (HR=1.73, 95%CI=1.19-2.52), 486-5p (HR=2.45, 95%CI=1.65-3.65), 506 (HR=2.07, 95%CI=1.33-3.23) have significantly poor OS (P<0.05). CONCLUSIONS In summary, miR-20b, 21, 106b, 125a, 137, 141, 145, 146a, 196a, 196b, 206, 214, 218, 451, 486-5p and 506 demonstrate significantly prognostic value. Among them, miR-20b, 125a, 137, 141, 146a, 196a, 206, 218, 486-5p and 506 are strong biomarkers of prognosis in GC.
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Affiliation(s)
- Yue Zhang
- 1 First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong, People's Republic of China
| | - Dong-Hui Guan
- 2 Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Rong-Xiu Bi
- 2 Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Jin Xie
- 2 Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Chuan-Hua Yang
- 3 Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
| | - Yue-Hua Jiang
- 4 Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong, People's Republic of China
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31
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Ding X, Liu J, Liu T, Ma Z, Wen D, Zhu J. miR-148b inhibits glycolysis in gastric cancer through targeting SLC2A1. Cancer Med 2017; 6:1301-1310. [PMID: 28440026 PMCID: PMC5463086 DOI: 10.1002/cam4.1008] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 12/03/2016] [Accepted: 12/15/2016] [Indexed: 02/06/2023] Open
Abstract
Although the molecular biology of GC has been well characterized, early diagnostic biomarkers and effective therapeutic options in gastric cancer are still under investigation. Here, we found that miR-148b expression decreased in human gastric cancer tissues compared with matched adjacent nontumor tissues by q-PCR analysis and in situ hybridization. Further investigation revealed that overexpression of miR-148b limited glycolysis including glucose consumption, lactate production in gastric cancer cell lines BGC-823 and MKN45. Bioinformatics prediction uncovered that a dedicated transporters solute carrier family 2 member 1 (SLC2A1), also called GLUT1, was the direct target of miR-148b. The target effects were further confirmed by luciferase assay and western blot analysis. Besides, a reverse correlation was observed between relative SLC2A1 and miR-148b expression in human GC tissues compared with matched adjacent nontumor tissues. Subsequently, SLC2A1 suppression by SLC2A1 siRNA or specific inhibitor restricted the reduced effects of glycolysis mediated by miR-148b while SLC2A1 overexpression abrogated the effect of miR-148b on glycolysis. Our findings provided new evidence of miR-148b in GC development through restraining glycolysis, highlighting the role of miR-148b as a new target for GC treatment.
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Affiliation(s)
- Xiangfu Ding
- Department of Thyroid SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Jingjing Liu
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Tianzhou Liu
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Zhiming Ma
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Dacheng Wen
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Jiaming Zhu
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
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32
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Sonohara F, Inokawa Y, Hayashi M, Kodera Y, Nomoto S. Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer. Oncol Lett 2017; 13:3363-3368. [PMID: 28529571 DOI: 10.3892/ol.2017.5912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/14/2017] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of cancer-related death, particularly in Asia. Epidemiological and other clinical studies have identified an association between a number of risk factors, including Helicobacter pylori, and GC. A number of studies have also examined genetic changes associated with the development and progression of GC. When considering the clinical significance of the expression of a specific gene, its epigenetic modulation should be considered. Epigenetic modulation appears to be a primary driver of changes in gastric tissue that promotes carcinogenesis and progression of GC and other neoplasms. The role of epigenetic modulation in GC carcinogenesis and progression has been widely studied in recent years. In the present review, recent results of epigenetic modulation associated with GC and their effects on clinical outcome are examined, with particular respect to DNA methylation, histone modulation and non-coding RNA. A number of studies indicate that epigenetic changes in the expression of specific genes critically affect their clinical significance and further study may reveal epigenetic changes as the basis for targeted molecular therapy or novel biomarkers that predict GC prognosis or extension of this often fatal disease.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.,Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
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33
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Abstract
The mammalian transcriptome includes a large number of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Some studies have reported that numerous kinds of miRNAs and lncRNAs have been implicated in playing key regulatory roles in the occurrence and development of digestive system malignances. Therefore, they are closely related to the clinical diagnosis, treatment and prognosis of digestive system malignances. This review focuses on the recent progress in research of miRNAs and lncRNAs in in digestive system malignancies and discusses their epigenetics roles as oncogenes or tumor suppressors. The current and future potential clinical applications of miRNAs and lncRNAs in digestive system malignancies are also discussed, with an aim to provide new ideas and means for the diagnosis, treatment and prognosis of digestive system malignancies.
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34
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Tsai MM, Wang CS, Tsai CY, Huang HW, Chi HC, Lin YH, Lu PH, Lin KH. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. Int J Mol Sci 2016; 17:945. [PMID: 27322246 PMCID: PMC4926478 DOI: 10.3390/ijms17060945] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/01/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022] Open
Abstract
Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan.
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Wei Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Pei-Hsuan Lu
- Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
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35
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Yan W, Qian L, Chen J, Chen W, Shen B. Comparison of Prognostic MicroRNA Biomarkers in Blood and Tissues for Gastric Cancer. J Cancer 2016; 7:95-106. [PMID: 26722365 PMCID: PMC4679386 DOI: 10.7150/jca.13340] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 10/18/2015] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) still keeps up high mortality worldwide with poor prognosis. Efficient and non-invasive prognostic biomarkers are urgently needed. MicroRNAs are non-coding RNAs playing roles in post-transcriptional gene regulation, which contribute to various biological processes such as development, differentiation and carcinogenesis. MicroRNA expression profiles have been associated with the prognosis and outcome in GC. MicroRNA prognostic biomarkers have been identified from blood or tissues samples, but with different prognostic features. Understanding the various roles of microRNAs in different sample sources of GC will provide deep insights into GC progression. In this review, we highlight the distinct prognostic roles of microRNAs biomarkers in blood and tissue according to their relationships with prognostic parameters, survival rates and target pathways. This will be useful for non-invasive biomarker development and selection in prognosis of GC.
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Affiliation(s)
- Wenying Yan
- 1. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; ; 2. Taicang Center for Translational Bioinformatics, Taicang 215400, China; ; 3. Center for Systems Biology, Soochow University, Suzhou 215006, China
| | - Laijun Qian
- 4. Daibu Center Hospital, Liyang, 213330, China
| | - Jiajia Chen
- 5. School of Chemistry, Biology and Material Engineering, Suzhou University of Science and Technology, Suzhou 215011, China
| | - Weichang Chen
- 1. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Bairong Shen
- 3. Center for Systems Biology, Soochow University, Suzhou 215006, China
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36
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Tang H, Li RP, Liang P, Zhou YL, Wang GW. miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway. Oncol Lett 2015; 10:681-686. [PMID: 26622553 DOI: 10.3892/ol.2015.3264] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 04/24/2015] [Indexed: 12/26/2022] Open
Abstract
In order to explore the regulation of the invasive ability of hepatocellular carcinoma cells and the underlying mechanism, mimics sequences of microRNA (miR)-125a (miR-125a-3p/5p) and scramble sequences (miR-125a-3p-s/5p-s) were transfected into human hepatocellular carcinoma cell lines, HCC-LM3 and HepG2, and the non-malignant epithelioid hepatic cell line QZG. To inhibit and upregulate the expression of miR-125a individually. Protein expression was detected by western blotting, and the cell proliferation and migration abilities were evaluated by soft agar colony formation and Transwell assay, respectively. It was revealed that the expression of miR-125a was downregulated in HepG2 and HCC-LM3 cells compared with that of QZG cells, and expression was markedly lower in HCC-LM3 cells than that in HepG2 cells (P<0.01). The colony formation and migration rates of the cells transfected with miR-125a-3p/5p were decreased compared with negative controls, but were increased in cells transfected with miR-125a-3p-3/5p-s (P<0.01). The protein and messenger RNA expression of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) was decreased following transfection with miR-125a-5p, whereas expression was increased compared with negative controls following transfection with miR-125a-5p-s (P<0.01). Furthermore, the proliferation and migration abilities of cells were attenuated following inhibition of the PI3K/AKT/mTOR pathway by LY294002. The results of the present study indicated that miR-125a inhibits the invasive ability of hepatocellular carcinoma cells via regulation of the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Hao Tang
- Department of Hepatobiliary Surgery, The 187 Hospital of Chinese People's Liberation Army, Haikou, Hainan 571159, P.R. China
| | - Rong-Ping Li
- Department of Emergency, The 187 Hospital of Chinese People's Liberation Army, Haikou, Hainan 571159, P.R. China
| | - Ping Liang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Third Military Medical University, Chongqing 400038, P.R. China
| | - Ya-Long Zhou
- Department of Hepatobiliary Surgery, The 187 Hospital of Chinese People's Liberation Army, Haikou, Hainan 571159, P.R. China
| | - Guang-Wei Wang
- Department of Hepatobiliary Surgery, The 187 Hospital of Chinese People's Liberation Army, Haikou, Hainan 571159, P.R. China
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37
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Dong Y, Li P, Ni Y, Zhao J, Liu Z. Decreased microRNA-125a-3p contributes to upregulation of p38 MAPK in rat trigeminal ganglions with orofacial inflammatory pain. PLoS One 2014; 9:e111594. [PMID: 25380251 PMCID: PMC4224409 DOI: 10.1371/journal.pone.0111594] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 10/03/2014] [Indexed: 11/23/2022] Open
Abstract
Orofacial inflammatory pain is a difficult clinical problem, and the specific molecular mechanisms for this pain remain largely unexplained. The present study aimed to determine the differential expression of microRNAs (miRNAs) and disclose the underlying role of miR-125a-3p in orofacial inflammatory pain induced by complete Freund's adjuvant (CFA). Thirty-two differentially expressed miRNAs were first screened using a microarray chip in ipsilateral trigeminal ganglions (TGs) following CFA injection into the orofacial skin innervated by trigeminal nerve, and a portion of them, including miR-23a*, -24-2*, -26a, -92a, -125a-3p, -183 and -299 were subsequently selected and validated by qPCR. The target genes were predicted based on the miRWalk website and were further analyzed by gene ontology (GO). Further studies revealed miR-125a-3p expression was down-regulated, whereas both the expression of p38 MAPK (mitogen-activated protein kinase) alpha and CGRP (calcitonin gene-related peptide) were up-regulated in ipsilateral TGs at different time points after CFA injection compared with control. Furthermore, mechanistic study revealed that miR-125a-3p negatively regulates p38 alpha gene expression and is positively correlated with the head withdrawal threshold reflecting pain. Luciferase assay showed that binding of miR-125a-3p to the 3′UTR of p38 alpha gene suppressed the transcriptional activity, and overexpression of miR-125a-3p significantly inhibited the p38 alpha mRNA level in ND8/34 cells. Taken together, our results show that miR-125a-3p is negatively correlated with the development and maintenance of orofacial inflammatory pain via regulating p38 MAPK.
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Affiliation(s)
- Yingchun Dong
- Department of Anesthesiology, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, China
- * E-mail: (YD); (ZL)
| | - Pengfei Li
- Department of Laboratory, Jiangsu Province Hospital of Traditional Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Yanhong Ni
- Central Laboratory, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, China
| | - Junjie Zhao
- Department of Periodontics, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, China
| | - Zhiqiang Liu
- Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, United States of America
- * E-mail: (YD); (ZL)
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38
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Huang TC, Renuse S, Pinto S, Kumar P, Yang Y, Chaerkady R, Godsey B, Mendell JT, Halushka MK, Civin CI, Marchionni L, Pandey A. Identification of miR-145 targets through an integrated omics analysis. MOLECULAR BIOSYSTEMS 2014; 11:197-207. [PMID: 25354783 DOI: 10.1039/c4mb00585f] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and protein synthesis. To characterize functions of miRNAs and to assess their potential applications, we carried out an integrated multi-omics analysis to study miR-145, a miRNA that has been shown to suppress tumor growth. We employed gene expression profiling, miRNA profiling and quantitative proteomic analysis of a pancreatic cancer cell line. In our transcriptomic analysis, overexpression of miR-145 was found to suppress the expression of genes that are implicated in development of cancer such as ITGA11 and MAGEA4 in addition to previously described targets such as FSCN1, YES1 and PODXL. Based on miRNA profiling, overexpression of miR-145 also upregulated other miRNAs including miR-124, miR-133b and miR-125a-3p, all of which are implicated in suppression of tumors and are generally co-regulated with miR-145 in other cancers. Using the SILAC system, we identified miR-145-induced downregulation of several oncoproteins/cancer biomarkers including SET, RPA1, MCM2, ABCC1, SPTBN1 and SPTLC1. Luciferase assay validation carried out on a subset of downregulated candidate targets confirmed them to be novel direct targets of miR-145. Overall, this multi-omics approach provided insights into miR-145-mediated tumor suppression and could be used as a general strategy to study the targets of individual miRNAs.
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Affiliation(s)
- Tai-Chung Huang
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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39
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Abstract
The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53’s tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.
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Affiliation(s)
- Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Huihui Li
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Longchang Jiang
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
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40
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Lerner C, Wemmert S, Schick B. Preliminary analysis of different microRNA expression levels in juvenile angiofibromas. Biomed Rep 2014; 2:835-838. [PMID: 25279155 DOI: 10.3892/br.2014.350] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 07/22/2014] [Indexed: 01/01/2023] Open
Abstract
Juvenile angiofibroma (JA) is a rare fibrovascular tumor affecting, almost exclusively, adolescent males. The finding of frequent β-catenin-mutations in JAs emphasized the significance of the Wnt-signaling pathway in tumor pathogenesis. In the last decade, microRNAs (miRNAs or miRs) have been found to be involved in cancer pathogenesis by post-transcriptional regulation of gene expression and have not been analyzed in JAs thus far. In the present study, the expression of 4 miRNAs (hsa-let-7d, hsa-miR-98, hsa-miR-125a-5p and hsa-miR-218) was analyzed in 13 JAs and 3 deepithelized inferior nasal turbinates that were used as control tissue. The miRNA expression of hsa-let-7d (P=0.158) and hsa-miR-98 (P=0.069) was not statistically different between the two tissue types, however, a significant decrease in expression was observed for hsa-miR-125a-5p (P=0.037) and hsa-miR-218 (P=0.009) in JAs compared to inferior nasal turbinates. As downregulation of miRNA 218 has been recently shown to result in stabilization and nuclear accumulation of β-catenin, the present data indicates further evidence for the importance of the Wnt-signaling pathway in JAs.
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Affiliation(s)
- Cornelia Lerner
- Department of Otolaryngology, Saarland University Medical Center, D-66421 Homburg/Saar, Germany
| | - Silke Wemmert
- Department of Otolaryngology, Saarland University Medical Center, D-66421 Homburg/Saar, Germany
| | - Bernhard Schick
- Department of Otolaryngology, Saarland University Medical Center, D-66421 Homburg/Saar, Germany
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41
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Shin VY, Chu KM. MiRNA as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol 2014; 20:10432-10439. [PMID: 25132759 PMCID: PMC4130850 DOI: 10.3748/wjg.v20.i30.10432] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the leading causes of cancer mortality in the world. Aberrant expression of microRNAs (miRNAs) is the hallmark of this disease. MiRNAs are endogenous non-coding RNAs that are involved in many biological processes (e.g., cell proliferation, differentiation, apoptosis, invasion and development) through gene repression. Deregulation of miRNA expression in gastric tumors and cancer cell lines have been documented to contribute in tumorigenesis, and the expression signature may correlate with different cancer types and clinicopathological features. Here, we summarized the updated gastric cancer-associated miRNAs and the downstream targets in the process of tumorigenesis. Recently, many researchers make use of the miRNA microarray platform to profile miRNA expression in gastric cancer and correlated with different clinical parameters. Its application on cancer diagnosis, prognosis and predicting treatment response rate are still underway and needs further investigation. Emerging roles of miRNAs with oncogenic or tumor suppressive properties in gastric tumorigenesis were discussed. Epigenetic silencing of miRNA by hypermethylation of promoter CpG island was also observed in gastric cancer. However, detailed mechanisms of how miRNAs regulate gene expression in gastric cancer has not been well studied. In this review, we highlight the up-to-date findings on the deregulated miRNAs in gastric cancer, and the potential use of miRNA in the clinical settings, such as diagnostic/prognostic markers and chemotherapeutic tools.
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42
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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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Ishiguro H, Kimura M, Takeyama H. Role of microRNAs in gastric cancer. World J Gastroenterol 2014; 20:5694-5699. [PMID: 24914330 PMCID: PMC4024779 DOI: 10.3748/wjg.v20.i19.5694] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 12/11/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Although gastric cancer (GC) is one of the leading causes of cancer-related death, major therapeutic advances have not been made, and patients with GC still face poor outcomes. The prognosis of GC also remains poor because the molecular mechanisms of GC progression are incompletely understood. MicroRNAs (miRNAs) are noncoding RNAs that are associated with gastric carcinogenesis. Studies investigating the regulation of gene expression by miRNAs have made considerable progress in recent years, and abnormalities in miRNA expression have been shown to be associated with the occurrence and progression of GC. miRNAs contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors, affecting cell proliferation, apoptosis, motility, and invasion. Moreover, a number of miRNAs have been shown to be associated with tumor type, tumor stage, and patient survival and therefore may be developed as novel diagnostic or prognostic markers. In this review, we discuss the involvement of miRNAs in GC and the mechanisms through which they regulate gene expression and biological functions. Then, we review recent research on the involvement of miRNAs in GC prognosis, their potential use in chemotherapy, and their effects on Helicobacter pylori infections in GC. A greater understanding of the roles of miRNAs in gastric carcinogenesis could provide insights into the mechanisms of tumor development and could help to identify novel therapeutic targets.
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Ninio-Many L, Grossman H, Levi M, Zilber S, Tsarfaty I, Shomron N, Tuvar A, Chuderland D, Stemmer SM, Ben-Aharon I, Shalgi R. MicroRNA miR-125a-3p modulates molecular pathway of motility and migration in prostate cancer cells. Oncoscience 2014; 1:250-261. [PMID: 25594017 PMCID: PMC4278297 DOI: 10.18632/oncoscience.30] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 04/28/2014] [Indexed: 12/21/2022] Open
Abstract
Fyn kinase is implicated in prostate cancer. We illustrate the role of miR-125a-3p in cellular pathways accounted for motility and migration of prostate cancer cells, probably through its regulation on Fyn expression and Fyn-downstream proteins. Prostate cancer PC3 cells were transiently transfected with empty miR-Vec (control) or with miR-125a-3p. Overexpression of miR-125a-3p reduced migration of PC3 cells and increased apoptosis. Live cell confocal imaging indicated that overexpression of miR-125a-3p reduced the cells' track speed and length and impaired phenotype. Fyn, FAK and paxillin, displayed reduced activity following miR-125a-3p overexpression. Accordingly, actin rearrangement and cells' protrusion formation were impaired. An inverse correlation between miR-125a-3p and Gleason score was observed in human prostate cancer tissues. Our study demonstrated that miR-125a-3p may regulate migration of prostate cancer cells.
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Affiliation(s)
- Lihi Ninio-Many
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel.,This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Lihi Ninio-Many, Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Hadas Grossman
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Mattan Levi
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Sofia Zilber
- Department of Pathology, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel
| | - Ilan Tsarfaty
- Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Israel
| | - Noam Shomron
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Anna Tuvar
- Department of Pathology, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel
| | - Dana Chuderland
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Salomon M Stemmer
- Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler School of Medicine, Tel Aviv University, Israel
| | - Irit Ben-Aharon
- Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler School of Medicine, Tel Aviv University, Israel
| | - Ruth Shalgi
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
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Li G, Qiu Y, Su Z, Ren S, Liu C, Tian Y, Liu Y. Genome-wide analyses of radioresistance-associated miRNA expression profile in nasopharyngeal carcinoma using next generation deep sequencing. PLoS One 2013; 8:e84486. [PMID: 24367666 PMCID: PMC3868612 DOI: 10.1371/journal.pone.0084486] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 11/14/2013] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Rapidly growing evidence suggests that microRNAs (miRNAs) are involved in a wide range of cancer malignant behaviours including radioresistance. Therefore, the present study was designed to investigate miRNA expression patterns associated with radioresistance in NPC. METHODS The differential expression profiles of miRNAs and mRNAs associated with NPC radioresistance were constructed. The predicted target mRNAs of miRNAs and their enriched signaling pathways were analyzed via biological informatical algorithms. Finally, partial miRNAs and pathways-correlated target mRNAs were validated in two NPC radioreisitant cell models. RESULTS 50 known and 9 novel miRNAs with significant difference were identified, and their target mRNAs were narrowed down to 53 nasopharyngeal-/NPC-specific mRNAs. Subsequent KEGG analyses demonstrated that the 53 mRNAs were enriched in 37 signaling pathways. Further qRT-PCR assays confirmed 3 down-regulated miRNAs (miR-324-3p, miR-93-3p and miR-4501), 3 up-regulated miRNAs (miR-371a-5p, miR-34c-5p and miR-1323) and 2 novel miRNAs. Additionally, corresponding alterations of pathways-correlated target mRNAs were observed including 5 up-regulated mRNAs (ICAM1, WNT2B, MYC, HLA-F and TGF-β1) and 3 down-regulated mRNAs (CDH1, PTENP1 and HSP90AA1). CONCLUSIONS Our study provides an overview of miRNA expression profile and the interactions between miRNA and their target mRNAs, which will deepen our understanding of the important roles of miRNAs in NPC radioresistance.
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Affiliation(s)
- Guo Li
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
| | - Yuanzheng Qiu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
| | - Zhongwu Su
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
| | - Shuling Ren
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
| | - Chao Liu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
| | - Yongquan Tian
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
| | - Yong Liu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China
- * E-mail:
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Xu X, Yang X, Xing C, Zhang S, Cao J. miRNA: The nemesis of gastric cancer (Review). Oncol Lett 2013; 6:631-641. [PMID: 24137382 PMCID: PMC3789097 DOI: 10.3892/ol.2013.1428] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 06/13/2013] [Indexed: 12/31/2022] Open
Abstract
microRNAs (miRNAs) are a group of small non-coding RNAs that are ~22 (18 to 25) nucleotides (nt) long and have been associated with a variety of diseases, including cancer. Increasing evidence indicates that miRNAs are essential in the development, diagnosis, treatment and prognosis of a variety of tumors. The utility of miRNAs as biomarkers for diagnosis and of target molecules for the treatment of cancers is increasingly being recognized. With the discovery of circulating miRNAs, a non-invasive approach for the diagnosis and treatment of cancer has been identified. This review summarizes the role of miRNAs in the development of different tumors, as well as a variety of other biological events. Moreover, this review focuses on analyzing the function and mechanism of gastric cancer-related miRNAs and investigates the importance of circulating miRNAs in gastric cancer, as well as their origin. Finally, this review lists a number of the problems that must be solved prior to miRNAs being used as reliable non-invasive tools for the diagnosis, treatment and prognosis of gastric cancer.
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Affiliation(s)
- Xiaohui Xu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, P.R. China
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Sánchez-Jiménez C, Carrascoso I, Barrero J, Izquierdo JM. Identification of a set of miRNAs differentially expressed in transiently TIA-depleted HeLa cells by genome-wide profiling. BMC Mol Biol 2013; 14:4. [PMID: 23387986 PMCID: PMC3600012 DOI: 10.1186/1471-2199-14-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 02/04/2013] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND T-cell intracellular antigen (TIA) proteins function as regulators of cell homeostasis. These proteins control gene expression globally at multiple levels in response to dynamic regulatory changes and environmental stresses. Herein we identified a micro(mi)RNA signature associated to transiently TIA-depleted HeLa cells and analyzed the potential role of miRNAs combining genome-wide analysis data on mRNA and miRNA profiles. RESULTS Using high-throughput miRNA expression profiling, transient depletion of TIA-proteins in HeLa cells was observed to promote significant and reproducible changes affecting to a pool of up-regulated miRNAs involving miR-30b-3p, miR125a-3p, miR-193a-5p, miR-197-3p, miR-203a, miR-210, miR-371-5p, miR-373-5p, miR-483-5p, miR-492, miR-498, miR-503-5p, miR-572, miR-586, miR-612, miR-615-3p, miR-623, miR-625-5p, miR-629-5p, miR-638, miR-658, miR-663a, miR-671-5p, miR-769-3p and miR-744-5p. Some up-regulated and unchanged miRNAs were validated and previous results confirmed by reverse transcription and real time PCR. By target prediction of the miRNAs and combined analysis of the genome-wide expression profiles identified in TIA-depleted HeLa cells, we detected connections between up-regulated miRNAs and potential target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analysis suggest that target genes are related with biological processes associated to the regulation of DNA-dependent transcription, signal transduction and multicellular organismal development as well as with the enrichment of pathways involved in cancer, focal adhesion, regulation of actin cytoskeleton, endocytosis and MAPK and Wnt signaling pathways, respectively. When the collection of experimentally defined differentially expressed genes in TIA-depleted HeLa cells was intersected with potential target genes only 7 out of 68 (10%) up- and 71 out of 328 (22%) down-regulated genes were shared. GO and KEGG database analyses showed that the enrichment categories of biological processes and cellular pathways were related with innate immune response, signal transduction, response to interleukin-1, glomerular basement membrane development as well as neuroactive ligand-receptor interaction, endocytosis, lysosomes and apoptosis, respectively. CONCLUSION All this considered, these observations suggest that individual miRNAs could act as potential mediators of the epigenetic switch linking transcriptomic dynamics and cell phenotypes mediated by TIA proteins.
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Affiliation(s)
- Carmen Sánchez-Jiménez
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, Cantoblanco, Madrid 28049, Spain
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