| Cancer is a complex genetic disease characterized by uncontrolled proliferation and inability of damaged cells to undergo cell death. Epigenetic alterations such as regulation by microRNAs have further expanded our understanding in cancer biology. microRNAs are small, non-coding RNA molecules that regulate gene expression, and many studies have shown that microRNAs are important biological molecules for controlling various cellular functions. microRNAs are dysregulated in human cancers where they can exert their effect as oncogenes or tumor suppressors. Therefore, their expression profiles have revealed a potential for their use as diagnostic, prognostic and predictive biomarkers of cancer. In this study, we identified miR-215 as a potential prognostic biomarker and miR-129 as a potential tumor suppressor and a novel therapeutic target in colorectal cancer. We showed that miR-215 levels were significantly decreased in tumors compared with corresponding normal tissues in patients diagnosed with stage II or stage III colorectal cancer. mRNA and protein expression of a critical miR-215 target, denticleless protein homolog (DTL), were significantly increased in colorectal tumors, further suggesting physiologic relevance of miR-215 mediated DTL suppression mechanism. Moreover, Kaplan-Meier survival analysis revealed that high levels of miR-215 expression were closely associated with poor overall survival in patients. In the second study, we discovered a novel mechanism mediated by miR-129 to trigger apoptosis by suppressing a key anti-apoptotic protein, BCL2. Ectopic expression of miR-129 promoted apoptosis, inhibited cell proliferation and caused cell cycle arrest in colorectal cancer cells. The intrinsic apoptotic pathway triggered by miR-129 was activated by the cleavage of caspase-9 and caspase-3. The expression of miR-129 was significantly and progressively down regulated in colorectal cancer tissue specimens compared with the adenomas and normal control samples. More importantly, we demonstrated that miR-129 increased the cytotoxic effect of the major chemotherapy drug in colorectal cancer, 5-fluorouracil, in vitro and in vivo. We expect that our findings will provide a better insight into the role of microRNAs in cancer and will hopefully allow us to design new strategies for the clinical use of these molecules as biomarkers or therapeutic targets. |
