Down-regulation of miR-138 promotes colorectal cancer metastasis via directly targeting TWIST2.

BACKGROUND: Colorectal cancer (CRC) is the most common digestive system malignancy. The molecular events involved in the development and progression of CRC remain unclear. Recently, more and more evidences have showed that deregulated miRNAs participate in colorectal carcinogenesis.

METHODS: The expression levels of miR-138 were first examined in CRC cell lines and tumor tissues by real-time PCR. The in vitro and in vivo functional effects of miR-138 were examined further. Luciferase reporter assays were conducted to confirm the targeting associations. Kaplan-Meier analysis and log-rank tests were performed to estimate the overall survival and disease free survival rate.

RESULTS: miR-138 was found to be down-regulated in human colorectal cancer tissues and cell lines. Ectopic expression of miR-138 resulted in a dramatic inhibition of CRC migration and invasion in vitro and in vivo. Twist basic helix-loop-helix transcription factor 2 gene (TWIST2) was identified as one of the functional target. Restoration of miR-138 resulted in a dramatic reduction of the expression of TWIST2 at both mRNA and protein levels by directly targeting its 3'-untranslated region (3'UTR). Up-regulation of TWIST2 was detected in CRC tumors compared with adjacent normal tissues (P < 0.001) and is inversely correlated with miR-138 expression. We also identified that down-regulation of miR-138 was associated with lymph node metastasis, distant metastasis, and always predicted poor prognosis.

CONCLUSION: These data highlight a pivotal role for miR-138 in the regulation of CRC metastasis by targeting TWIST2, and suggest a potential application of miR-138 in prognosis prediction and CRC treatment.