SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis
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AbstractSlit-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/beta-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/beta-catenin pathway.
Acceptance Date05/09/2017
All Author(s) ListHuang TT, Zhou YH, Zhang JL, Wong CC, Li WL, Kwan JSH, Yang R, Chan AKY, Dong YJ, Wu F, Zhang B, Cheung AHK, Wu WKK, Chen ASL, Yu J, Wong N, Kang W, To KF
Journal nameOncogene
Year2018
Month3
Volume Number37
Issue Number9
PublisherNature Publishing Group
Pages1159 - 1174
ISSN0950-9232
eISSN1476-5594
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesBiochemistry & Molecular Biology;Oncology;Cell Biology;Genetics & Heredity;Biochemistry & Molecular Biology;Oncology;Cell Biology;Genetics & Heredity

Last updated on 2021-16-09 at 01:14