MicroRNA-187, a downstream effector of TGFβ pathway, suppresses Smad-mediated epithelial-mesenchymal transition in colorectal cancer

Constitutive overactivation of TGF beta signaling is a common event in human cancer progression and acts as a major inducer of epithelial-mesenchymal transition (EMT). In pre-metastatic colorectal cancer (CRC) cells, however, this cascade is tightly controlled and the underlying mechanism in TGF beta stimulated hyperactivation of downstream Smad pathway remains elusive. In this study, expression of miR-187 was downregulated in colorectal cancer (CRC) compared with adjacent normal tissues. miR-187 could suppress the formation of aggressive phenotype in CRC and inactivate Smad pathway, thus preventing EMT. TOM stimulation significantly suppressed the expression of miR-187, and overexpressed miR-187 counteracted the influence of TGF beta on cell phenotype and downstream pathway. Furthermore, we found that miR-187 directly suppressed the expression of SOX4, NT5E and PTK6, which were identified as essential upstream effectors of Smad pathway. Together with the fact that high SOX4 or NT5E levels were associated with poor prognosis, we also demonstrated that downregulation of miR-187 was closely related to tumor metastasis and poor prognosis in CRC. These findings revealed a plausible mechanism for sustained TGF beta activation in cancer progression and might have suggested a novel miR-187-based clinical intervention target for patients with advanced CRC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.