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

Background: Abnormal 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.

Methods: The 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.

Results: We 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.

Conclusion: These results provide that miR-503 expression acts as a predictor for GC prognosis and may have a potential application in GC therapy.