The role of XBP1s in the metastasis and prognosis of hepatocellular carcinoma

Abstract

Tumor metastasis and recurrence are the primary contributors to poor prognosis in patients with hepatocellular carcinoma (HCC). The epithelial-mesenchymal transition (EMT) of tumor cells is the predominant mechanism of HCC progression. XBP1s is a newly discovered molecule involved in the endoplasmic reticulum (ER) stressresponse, which is an adaptive response and defense mechanism in cells that enablessurvival under adverse conditions. Abnormally high XBP1sexpression has been found in tumor cells, but the role of XBP1sin HCC progression remains unclear. We found that the expression of XBP1s in HCC cell lines and tissuesamples was higher than that in control cells and tissuesamples. Clinicopathological analysis showed that the expression of XBP1s was closely correlated with distant metastasis and poor prognosis in HCC. In vivo and invitro experiments confirmed that the overexpression of XBP1s promoted EMT and metastasis in HCC cells. XBP1ssilencing attenuated cellular migration and development of the EMT phenotypein vitro. Through further study to elucidate the molecular mechanism underlying the promotion ofEMT by XBP1s in HCC cells, we confirmed that XBP1s could mediate the expression of Twist. In HCC cells, XBP1s enhanced the expression of Twist and Snail, resulting in a subsequent reduction in the expression of E-cadherin, a contributor to cell-cell adhesion. Overall, this study reveals a novel XBP1s/Twist/Snail axis that mediates EMT in HCC cells and the invasion and metastasis of HCC.