MicroRNA-200b Stimulates Tumour Growth in TGFBR2-Null Colorectal Cancers by Negatively Regulating p27/kip1

Colorectal cancer (CRC) remains the most common malignancy worldwide. TGF-1 is often overexpressed in late stages of colorectal carcinogenesis and promotes tumour growth and metastasis. Several reports have verified that the loss of functional TGFBRII expression contributed to escape the tumour suppressor activity of TGF-1 and that the epithelial-to-mesenchymal transition (EMT) responded to TGF-1 involved in tumour invasion and metastasis. However, the mechanisms by which TGF-1 confers a growth advantage to TGFBRII-null colorectal cancer cells have not been elucidated. MicroRNAs (miRNAs) are post-transcriptional inhibitory regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for miR-200b in colorectal cancer. MiR-200b was highly expressed in TGFBRII-null tumour tissues and colorectal cancer cell lines and positively correlated with cell proliferation in tumour tissues and cell lines. In contrast, decreasing the miR-200b level in TGFBRII-null cells suppressed cell proliferation and cell cycle progression. Furthermore, in vivo studies also suggested a stimulating effect of miR-200b on TGFBRII-null cell-derived xenografts. CDKN1B (p27/kip1) and RND3 (RhoE) have miR-200b binding sequences within their 3 untranslated regions and were confirmed to be direct targets of miR-200b using fluorescent reporter assays. Meanwhile, CDKN1B (p27/kip1) played a role in miR-200b-stimulated TGFBR-null CRC. This study suggests that miR-200b plays a tumour-promoting role by targeting CDKN1B (p27/kip1) in CRCs. J. Cell. Physiol. 229: 772-782, 2014. (c) 2013 Wiley Periodicals, Inc.