Abstract
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 β-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 β-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 β-catenin signaling pathway. These findings suggest potential targets for the treatment of HCC and therefore merit further investigation.
Highlights
Hepatocellular carcinoma (HCC), which accounts for 85–90% of all liver cancers, is the second leading cause of cancer-related mortality worldwide (Forner et al, 2012)
Western blot and qRT-PCR analysis of Tribbles 1 (TRIB1) and p53 expression in the HCC cell lines SMMC7721(wide type p53), HepG2(wide type p53), and Huh7(mutant p53 Y220C) and the normal liver cell line LO2 showed that TRIB1 expression was significantly higher and p53 expression was significantly lower in HCC cells than in normal liver cells (Figures 1D,E)
The present study examined the role of miR-23a and its target TRIB1 in HCC and elucidated a potential underlying mechanism that would involve the modulation of p53 and the β-catenin pathway
Summary
Hepatocellular carcinoma (HCC), which accounts for 85–90% of all liver cancers, is the second leading cause of cancer-related mortality worldwide (Forner et al, 2012). Epithelial mesenchymal transition (EMT), by which polarized epithelial cells acquire a mesenchymal phenotype characterized by fibroblastoid-like shape, high motility, and increased invasive capacity, plays a critical role in the invasion and metastasis of cancer cells (Kalluri and Weinberg, 2009). The transforming growth factor beta (TGF-β) and wnt/β-catenin signaling pathways play important roles in EMT. Β-catenin accumulates in the nucleus and binds to the transcription factor TCF/LEF, modulating the transcription of genes involved in EMT (Gilles et al, 2003; Yook et al, 2006). As a result of physical interactions, TRIB1 inhibits the tumor suppressor p53, which is the most frequently mutated gene in HCC and plays a critical role in many cancers (Miyajima et al, 2015). As a result of physical interactions, TRIB1 inhibits the tumor suppressor p53, which is the most frequently mutated gene in HCC and plays a critical role in many cancers (Miyajima et al, 2015). p53 functions as a transcriptional factor, activating genes involved in cell-cycle progression, senescence, and apoptosis (Kruse and Gu, 2009)
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