SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis
| Autor: | Alvin Ho-Kwan Cheung, Yuhang Zhou, William K.K. Wu, Ka Fai To, Bin Zhang, Wei Kang, Yujuan Dong, Jun Yu, Nathalie Wong, Jinglin Zhang, Feng Wu, Alfred S. L. Cheng, Tingting Huang, Aden K. Y. Chan, Johnny S. H. Kwan, Rui Yang, Chi Chun Wong, Weilin Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Apoptosis Biology medicine.disease_cause Article 03 medical and health sciences Mice 0302 clinical medicine Western blot Stomach Neoplasms microRNA Genetics medicine Biomarkers Tumor Tumor Cells Cultured Animals Humans Molecular Biology Cell Proliferation Regulation of gene expression Gene knockdown Oncogene medicine.diagnostic_test Cell growth GTPase-Activating Proteins Wnt signaling pathway Oncogenes Prognosis Molecular biology Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Survival Rate MicroRNAs 030104 developmental biology 030220 oncology & carcinogenesis Neoplasm Recurrence Local |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Slit-Robo GTPase-activating protein 1 (SRGAP1) functions as a GAP for Rho-family GTPases and downstream of Slit-Robo signaling. We aim to investigate the biological function of SRGAP1 and reveal its regulation by deregulated microRNAs (miRNAs) in gastric cancer (GC). mRNA and protein expression of SRGAP1 were examined by quantitative reverse transcription PCR (qRT-PCR) and western blot. The biological role of SRGAP1 was demonstrated through siRNA-mediated knockdown experiments. The regulation of SRGAP1 by miR-340 and miR-124 was confirmed by western blot, dual luciferase activity assays and rescue experiments. SRGAP1 is overexpressed in 9 out of 12 (75.0%) GC cell lines. In primary GC samples from TCGA cohort, SRGAP1 shows gene amplification in 5/258 (1.9%) of cases and its mRNA expression demonstrates a positive correlation with copy number gain. Knockdown of SRGAP1 in GC cells suppressed cell proliferation, reduced colony formation, and significantly inhibited cell invasion and migration. Luciferase reporter assays revealed that SRGAP1 knockdown significantly inhibited Wnt/β-catenin pathway. In addition, SRGAP1 was found to be a direct target of two tumor-suppressive miRNAs, miR-340 and miR-124. Concordantly, these two miRNAs were downregulated in primary gastric tumors and these decreasing levels w5ere associated with poor outcomes. Expression of miR-340 and SRGAP1 displayed a reverse relationship in primary samples and re-expressed SRGAP1, rescued the anti-cancer effects of miR-340. Taken together, these data strongly suggest that, apart from gene amplification and mutation, the activation of SRGAP1 in GC is partly due to the downregulation of tumor-suppressive miRNAs, miR-340 and miR-124. Thus SRGAP1 is overexpressed in gastric carcinogenesis and plays an oncogenic role through activating Wnt/β-catenin pathway. |
| Databáze: | OpenAIRE |
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