Journal
FRONTIERS IN PHYSIOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2017.00789
Keywords
hepatocellular carcinoma; Tribbles 1; microRNA-23a; tumor suppressor p53; beta-catenin signaling pathway
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Funding
- Key disciplines Group Construction Project of Pudong Health Burea of Shanghai [PWZxq2014-12]
- Natural Science Foundation of China [81571718]
- Shanghai Pudong Science and Technology Committee Foundation [PKJ2016-Y50]
- Budgetary fund of Shanghai University of TCM [2015YSN59]
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Hepatocellular carcinoma (HCC) is a common malignancy associated with a high risk of recurrence and metastasis and a poor prognosis. Here, we examined the involvement of the pseudokinase Tribbles 1 (TRIB1), a scaffold protein associated with several malignancies, in HCC and investigated the underlying mechanisms. TRIB1 was upregulated in HCC tissues and cell lines in correlation with low levels of p53. TRIB1 gain and loss of function experiments indicated that TRIB1 promoted HCC cell viability concomitant with the downregulation of p53, and induced HCC cell migration, invasion, and epithelial-mesenchymal transition. TRIB1 was identified as a target of microRNA-23a (miR-23a), and miR-23a overexpression downregulated TRIB1 and upregulated p53 in HCC cells. Ectopic expression of TRIB1 upregulated beta-catenin and its effectors c-myc and MMP-7 in a p53-dependent manner. TRIB1 silencing inhibited tumor growth and promoted apoptosis in vivo via a mechanism that would involve the modulation of p53 and beta-catenin signaling. The present results indicate that TRIB1 promotes HCC tumorigenesis and invasiveness via a feedback loop that involves the modulation of its expression by miR-23a with the likely downregulation of p53, and suggest the involvement of the beta-catenin signaling pathway. These findings suggest potential targets for the treatment of HCC and therefore merit further investigation.
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