MiR-181a, a new regulator of TGF-β signaling, can promote cell migration and proliferation in gastric cancer

Transforming growth factor-beta (TGF-beta) signaling pathway plays pivotal roles in various types of cancer. TGF-beta receptor 2 (TGF beta R2) contains a kinase domain that phosphorylates and activates the downstream of the TGF-beta signaling pathway. Our previous microarray analysis revealed marked changes in miR-181a expression in gastric cancers, and the bioinformatics analysis suggested that miR-181a negatively regulated TGF beta R2. In order to verify the effect of miR-181a on TGF beta R2 and clarify the influence of miR-181a on the migration and proliferation of gastric cancer, studies in gastric cancer cell lines and xenograft mouse models were carried out. We found that a reduced expression of TGF beta R2 and an increased expression miR-181a in gastric cancer tissues compared to adjacent noncancerous tissues. A luciferase reporter assay confirmed that TGF beta R2 was a target of miR-181a. In addition, we found that miR-181a mimics, which increased the level of miR-181a, downregulated the expression of TGF beta R2 in the gastric cancer cell line SGC-7901. Moreover, both the overexpression of miR-181a and the downregulation of TGF beta R2 promoted the migration and proliferation of SGC-7901 cells. Conversely, SGC-7901 cell migration and proliferation were inhibited by the downregulation of miR-181a and the overexpression of TGF beta R2. Furthermore, the increased expression of miR-181a and the decreased expression of TGF beta R2 also enhanced the tumor growth in mice bearing gastric cancer. Our results herein indicated that miR-181a promoted the migration and proliferation of gastric cancer cells by downregulating TGF beta R2 at the posttranscriptional level. The present study suggests that miR-181a is a novel negative regulator of TGF beta R2 in the TGF-beta signaling pathway and thus represents a potential new therapeutic target for gastric cancer.