Tumor-suppressive function of micro-RNA mir-196a in colorectal cancer
2007
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
2183
Background : MicroRNAs as mir-196a are small endogenous RNAs, playing important roles in posttranscriptional gene expression regulation. Interestingly, siRNA-microarray analyses previously detected mir-196a transcription in human cancer cells. In mice, HoxC8 mRNA was restricted by mir-196a and mir-196a was furthermore predicted to interact with HoxD8 and HoxA7 mRNAs. As Hox genes are master regulators of proliferation and differentiation during embryogenesis, we analyzed the mir-196a function in human colorectal cancer and the clinical relevance of its target gene expression.
Methods : Colorectal cancer cell lines SW480, SW620 and HT29 were transientely transfected with mir-196a. Regulation of HoxB8, HoxD8 and HoxA7 was analyzed on a trancriptional and translational level. Transfected cells were applied in diverse functional assays (proliferation, adhesion, cell cycle analysis, migration, apoptosis). HoxB8, D8 and A7 transcription was evaluated in 100 colorectal cancer samples by PCR and correlated with clinico-pathological parameters.
Results: Transfection of SW480 and SW620 resulted in a rapid down-regulation of HoxB8, HoxD8 and HoxA7 expression. However, in HT29 no regulation could be observed. Mir-196a did not impact on proliferation, cell cycle or apoptosis but did increase cellular adhesion and inhibited migration. Mir-196a target gene HoxA7 and HoxD8 did not impact on clinical or pathological parameters. However, HoxB8 transcription, which was observed in 50% of samples, positively correlated with locally advanced and destructive primary cancers as indicated by the T-status (P<0.01).
Conclusion: HoxB8, HoxD8 and HoxA7 are restriction targets of mir-196a in human cellular systems. Mir-196a inhibits migration and enhances cellular adhesion in vitro . Moreover, HoxB8 enhances local progression of colorectal cancers in vivo . Both results implicate a tumor-suppressive function of mir-196a.
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