Dexamethasone-stimulated glucocorticoid receptor signaling positively regulates the endoplasmic reticulum-associated degradation (ERAD) mechanism in hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma is one of the most common types of primary liver cancer in adults and also it is the third leading cause of cancer-related deaths worldwide. Although there are various treatment options such as surgery, radiation, targeted drug therapy, immunotherapy and chemotherapy, most hepatocellular carcinomas are highly resistant to systemic treatments. Today, the molecular pathogenesis of hepatocellular carcinoma remains largely obscure. Therefore, there is a need for detailed research for the characterization of molecular signaling networks related to the development of hepatocellular carcinoma. Recent studies have attention to the hormonal regulation of hepatocellular carcinoma cells mediated by systemic hormones such as glucocorticoids. However, glucocorticoid-mediated regulation of endoplasmic reticulum-associated degradation (ERAD) and unfolded protein response (UPR), which are known to be important survival mechanisms for cancer cells remains unknown in hepatocellular carcinoma. In the present study, we showed that dexamethasone-induced glucocorticoid receptor signaling mediated advanced regulation of ERAD and UPR signaling in hepatocellular carcinoma cells. Our findings indicated that glucocorticoid signaling positively regulated mRNA and protein levels of ERAD components and also protein kinase RNA-like ER Kinase (PERK) and inositol-requiring enzyme 1⍺ (IRE1⍺) branches of UPR signaling are accompanied by the glucocorticoid signaling. In addition, putative glucocorticoid response elements (GREs) were determined in the promoter regions of ERAD members in in-silico analyses. Additionally, silencing of ERAD components significantly reduced the tumorigenic features of hepatocellular carcinoma cells, including cell proliferation, metastasis, invasion and 3D tumor formation. Collectively, these results reveal a novel pattern of regulation of ERAD components by glucocorticoid-mediated in human hepatocellular carcinoma cells.