Background: Activated hepatic stellate cells (HSCs) are the major subtype of stromal cells in the liver tumor microenvironment which can promote the growth and migration of hepatocellular carcinoma (HCC) cells. Indeed, senescent and cancer-associated fibroblasts express numerous inflammatory and tumor promoting factors that are collectively referred to as the senescence-associated secretory phenotype (SASP). In the present study, we investigated the mechanisms of bile acid-mediated induction of HSC activation as the SASP in hypoxic conditions.Methods: The immortalized human stellate cells (LX-2 cells) were used in this study. Invasion assay were done to evaluate the invasion of HSCs either in a normoxic or hypoxic conditions. IL-8 mRNA was quantitated using real-time PCR. To investigate the mechanisms, western blot analyses were performed either in a normoxic or hypoxic conditions.Results: Bile acid significantly increased the invasion of HSCs in hypoxic conditions as compared to that in normoxic conditions by IL-8 expression, which is an inflammatory cytokine involved in tumor promotion and key component of the SASP. Bile acid increased protein expressions of the mesechymal markers including α-SMA and vimentin in HSCs. Moreover, bile acid increased the protein expressions of Mcl-1 and cyclooxygenase-2 (COX-2) in HSCs. The inhibitors of either Mcl-1 induction by siRNA transfection or COX-2 activity by celecoxib decreased the bile acid-mediated HSC invasion in hypoxic conditions. Mcl-1 and COX-2 induction was found to be due to transcriptional enhancement dependent on TGR-5 activation.Conclusions: Bile acid-mediated induction of HSC activation and invasion as the SASP was due to TGR-5 dependent overexpression of Mcl-1 and COX-2, which may lead to HCC progression in hypoxic conditions.
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Bile acid-mediated induction of hepatic stellate cell activation and invasion via Mcl-1 and COX-2 in hypoxic conditions
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