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MiR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition.

ABSTRACT: Recently, the role of miR-29b in colorectal carcinoma (CRC) development appears to be controversial. Until now, the expression and function of miR-29b in CRC have not been clarified clearly. We showed that decreased expression of miR-29b usually occurred in CRC cell lines and tissue samples. Loss- and gain-of-function assays in vitro revealed suppressive effects of miR-29b on cell proliferation and migration. Endogenous overexpression of miR-29b was sufficient to suppress aggressive behavioral phenotypes in mice. Proteomic analysis showed that miR-29b involved in integrate several key biological processes. In addition, miR-29b mediated the inhibition of epithelial-mesenchymal transition (EMT) and the inactivation of mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signal transduction pathway. Further studies found that T lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct target of miR-29b. In contrast to the phenotypes induced by miR-29b restoration, Tiam1-induced cell proliferation and migration partly rescued miR-29b-mediated biological behaviors. Our results illustrated that miR-29b as a suppressor has a critical role in CRC progression, which suggests its potential role in the molecular therapy of patients with advanced CRC.

SUBMITTER: Wang B

PROVIDER: S-EPMC4123095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.MethodsThe current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.ResultsWe demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3'-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.ConclusionsOur study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

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MiR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition.

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