Abstract
The transforming growth factor beta (TGF-β) signaling pathway is a tumor-suppressor pathway that is commonly inactivated in colorectal cancer (CRC). The inactivation of TGFBR2 is the most common genetic event affecting the TGF-β signaling pathway. However, the mechanism by which cancer cells downregulate TGFBR2 is unclear. In this study, we found that the TGFBR2 protein levels were consistently upregulated in CRC tissues, whereas its mRNA levels varied in these tissues, suggesting that a post-transcriptional mechanism is involved in the regulation of TGFBR2. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that potentially target TGFBR2. We identified the specific targeting site of miR-135b in the 3’-untranslated region (3’-UTR) of TGFBR2. We further identified an inverse correlation between the levels of miR-135b and TGFBR2 protein, but not mRNA, in CRC tissue samples. By overexpressing or silencing miR-135b in CRC cells, we experimentally validated that miR-135b directly binds to the 3’-UTR of the TGFBR2 transcript and regulates TGFBR2 expression. Furthermore, the biological consequences of the targeting of TGFBR2 by miR-135b were examined using in vitro cell proliferation and apoptosis assays. We demonstrated that miR-135b exerted a tumor-promoting effect by inducing the proliferation and inhibiting the apoptosis of CRC cells via the negative regulation of TGFBR2 expression. Taken together, our findings provide the first evidence supporting the role of miR-135b as an oncogene in CRC via the inhibition of TGFBR2 translation.
Highlights
Colorectal cancer (CRC) is currently the third most common malignancy and the second leading cause of cancer-related death worldwide [1]
After measuring the protein levels of TGFBR2 in five paired CRC and normal adjacent tissues, we found that the TGFBR2 protein levels were dramatically reduced in the CRC tissues compared to the normal adjacent tissues (Fig 1A and 1B)
This disparity between the protein and mRNA expression of TGFBR2 in CRC strongly suggests that a post-transcriptional mechanism is involved in the regulation of TGFBR2
Summary
Colorectal cancer (CRC) is currently the third most common malignancy and the second leading cause of cancer-related death worldwide [1]. The accumulation of genetic and epigenetic alterations mediates CRC formation and progression by deregulating key signaling pathways in cancer cells [2,3]. The TGF-β signaling pathway acts as a tumor-suppressor during the early stage of CRC, which is often inactivated via the downregulation of TGFBR2 [7]. The inactivation of TGFBR2 due to genetic mutation or methylation was reported to primarily occur in microsatellite-instable CRC because of DNA mismatch repair defects [12,13,14]. The mechanism underlying non-mismatch repair-deficient CRC remains unclear. These observations suggest that other molecular mechanisms may be involved in the downregulation of TGFBR2; this hypothesis requires further investigation
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