Abstract
The molecular mechanisms underlying colorectal cancer (CRC) development remain elusive. In this study, we examined the miRNA and mRNA expressions in the adenoma-carcinoma sequence (ACS), a critical neoplastic progression in CRC development. We found that miR-137 was down-regulated in all adenoma and carcinoma tissues. Low miR-137 levels were correlated negatively with tumor progression and metastasis. Then we identified the inhibition effect of the miR-137 in CRC development, both in CRC cell lines and mouse models. MiR-137 was shown to control CRC cell proliferation, colony formation, migration and invasion and to control tumor growth and metastasis. We further confirmed the negative association between miR-137 and c-Met expression and thus validated this important oncogene as the target of miR-137 in CRC. In addition, we found a DNA methyl-CpG-binding protein, Mecp2, was up-regulated in ACS tissues via mRNA sequencing. Further experiment showed that miR-137 expression in CRC was subjected to epigenetic regulation mediated by Mecp2. We also confirmed c-Met expression can be up-regulated by silencing of miR-137 and suppressed by coexpression of Mecp2 and miR-137. These findings highlight the critical role of miR-137-c-Met nexus in CRC development and reveal Mecp2-regulated epigenetic silence causes the downregulation of miR-137 in colorectal adenoma and carcinoma.
Highlights
MicroRNA is a class of short (18 to 24 nucleotides), non-protein-coding RNA that regulates the translation and degradation of messenger RNA via interacting with its 3′-untranslated region (3′ UTR)[5]
A small RNA sequencing analysis of 18 colorectal adenoma-carcinoma sequence (ACS) tissues from 6 patients was conducted to study the effect of miRNA profile in regulating human colorectal ACS and colorectal cancer (CRC) progression
When the clinicopathological implication of miR-137 was analyzed in CRC patients it is found that low miR-137 levels were negatively correlated to tumor TNM stage (Fig. 1d; P = 0.019) and metastasis (Fig. 1e; P = 0.017)
Summary
MicroRNA (miRNA) is a class of short (18 to 24 nucleotides), non-protein-coding RNA that regulates the translation and degradation of messenger RNA (mRNA) via interacting with its 3′-untranslated region (3′ UTR)[5]. Different patterns of miRNA-expression have been identified in different cancer types[6]. Body of research showed that miRNA alternations played a key role in the development of various types of cancer. Little is known about the functional role of miRNA in consecutive colorectal ACS and CRC progressions. We examined the expression of miR-137 in ACS and explored its role in the regulation of CRC cell function. MiRNA-137-mediated c-Met expression in cells and the underlying mechanism of miRNA-137 alternation in colorectal ACS were investigated
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