Abstract
P4HB and GRP78 are molecular chaperones involved in cellular response to ER stress. They have been linked to cancer progression; however, their roles in hepatocellular carcinoma (HCC) are largely unclear. In this study, we found that P4HB is overexpressed in human HCC tissues and cell lines. Higher tumoral P4HB levels are correlated with more advanced disease and poorer survival. GRP78 expression is inversely correlated with P4HB in human HCC tissues, and downregulated by P4HB in HCC cell lines. P4HB overexpression promotes HCC cell growth, migration, invasion and epithelial-to-mesenchymal transition (EMT) in vitro. GRP78 overexpression not only inhibits HCC cell growth, migration, invasion and EMT, but also antagonizes the oncogenic effects of P4HB overexpression. Furthermore, P4HB silencing inhibits HCC tumorigenesis in vivo. Taken together, our results provided evidence that P4HB promotes HCC progression through downregulation of GRP78 and subsequent upregulation of EMT.
Highlights
Tumor cells are often exposed to hypoxia and nutrient deprivation
We found that P4HB is upregulated in human hepatocellular carcinoma (HCC)
We found that P4HB promotes HCC cell growth, migration, and invasion in vitro and tumor formation in vivo
Summary
Tumor cells are often exposed to hypoxia and nutrient deprivation These unfavorable conditions result in accumulation of unfolded proteins in the ER, causing ER stress. GRP78 promotes tumor growth, survival and metastasis; and is generally considered to play an oncogenic role in cancer [6]. GRP78 knockdown increases the migratory ability of colon cancer and hepatocellular carcinoma (HCC) cells through upregulation of epithelialto-mesenchymal transition (EMT) [8, 9]. These results suggest that the role of GRP78 in tumorigenesis can be context-dependent
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