MiR-503 suppresses cell proliferation and invasion of gastric cancer by targeting HMGA2 and inactivating WNT signaling pathway

Abstract

BackgroundAbnormal expression of microRNAs (miRNAs) is related to human carcinogenesis. Although previous studies have shown that miR-503 expression in gastric cancer (GC) is downregulated, however, the underlying molecular mechanism for miR-503 involved in gastric cancer development is still largely unknown.MethodsThe relative expression of miR-503 in GC tissues and adjacent normal tissues was examined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analyses. In vitro, cell proliferation and invasion were evaluated by using CCK8, cell colony and transwell invasion assays. In vivo, xenograft tumor model was constructed to assess miR-503 expression whether affects tumor growth or not. Luciferase reporter assay, qRT-PCR and western blot assay were used to demonstrate HMGA2 is a target of miR-503.ResultsWe demonstrated that miR-503 expression was significantly downregulated in GC tissues and cell lines compared to adjacent normal tissues and normal gastric mucosa cell lines, respectively. Lower miR-503 expression associated with tumor size, lymph node metastasis, and predicted a poor overall survival (OS) time in GC patients. Subsequently, in vitro, gain-function and loss-function assays confirmed that miR-503 overexpression significantly suppressed GC cell proliferation, colony formation and cell invasion, while decreased miR-503 expression had an adverse effect in GC cells. Furthermore, we found that miR-503 specifically targeted the 3′-UTR regions of HMGA2 mRNA and suppressed its protein expression. Overexpression of HMGA2 could reverse the miR-503 mediated inhibition of GC cell proliferation and invasion. In vivo, miR-503 overexpression dramatically reduced tumor growth. Moreover, we demonstrated that miR-503 suppressed WNT/β-catenin signaling by elevating GSK-3β and p-β-catenin expression, but decreased p-GSK-3β and β-catenin expression in GC cells.ConclusionThese results provide that miR-503 expression acts as a predictor for GC prognosis and may have a potential application in GC therapy.