TGF-β upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1

Abstract

Transforming growth factor β (TGF-β) plays important roles in tumor metastasis by regulating miRNAs expression. miR-182 is an important molecule in the regulation of cancer progression. The aim of the study is to assess the role of miR-182 in TGF-β-induced cancer metastasis. In the present study, we found that miR-182 levels are significantly upregulated in GBC tissues compared with normal controls, and miR-182 expression is remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. TGF-β induces miR-182 expression in GBC cells, and overexpression of miR-182 promotes GBC cell migration and invasion, whereas miR-182 inhibition suppresses TGF-β-induced cancer cell migration and invasion. The blockage of miR-182 by a specific inhibitor effectively inhibits pulmonary metastases in vivo. We further identified that the cell adhesion molecule1 (CADM1) is a new target gene of miR-182. miR-182 negatively regulates CADM1 expression in vitro and in vivo. Importantly, re-expression of CADM1 in GBC cells partially abrogates miR-182-induced cell invasion. miR-182 is an important mediator of GBC metastasis, thus offering a new target for the development of therapeutic agents against GBC.