3309

HSPA5

Invasion is a major characteristic of hepatocellular carcinoma and one of the main causes of refractory to treatment. We have previously reported that GRP78 promotes the invasion of hepatocellular carcinoma although the mechanism underlying this change remains uncertain. In this paper, we explored the role of the cell surface GRP78 in the regulation of cancer cell invasion in hepatocellular carcinoma cells. We found that neutralization of the endogenous cell surface GRP78 with the anti-GRP78 antibody inhibited the adhesion and invasion in hepatocellular carcinoma cell lines Mahlavu and SMMC7721. However, forced expression of the cell surface GRP78 facilitated the adhesion and invasion in SMMC7721. We further demonstrated that inhibition of the endogenous cell surface GRP78 specifically inhibited the secretion and activity of MMP-2 but did not affect the secretion and activity of MMP-9. We also found that inhibition of the cell surface GRP78 increased E-Cadherin expression and decreased N-Cadherin level. On the contrary, forced expression of the cell surface GRP78 increased N-Cadherin expression and decreased E-Cadherin level, suggesting that the cell surface GRP78 plays critical role in the regulation of EMT process. These findings suggest that the cell surface GRP78 plays a stimulatory role in the invasion process and may be a potential anti-invasion target for the treatment of hepatocellular carcinoma.

Glucose-regulated protein of 78kD (GRP78) is a multifunctional protein belonging to the heat shock protein 70 family. Overexpression of GRP78 triggered by environmental and physiological stresses is positively correlated with the occurrence and progression of various tumors, but the molecular mechanisms have not been well established. The present study indicated that overexpression of GRP78 in colon cancer cells could promote cell-matrix adhesion through the upregulation of fibronectin, integrin-beta1 and phosphorylated FAK. Meanwhile, it resulted in a visible epithelial-mesenchymal transition in DLD1 cells, and the Snail-2 played the key role during the process. More importantly, the data indicated that GRP78 overexpression facilitated the expression and secretion of TGF-beta1, which further activated the downstream Smad2/3 signaling module to effectuate the cell-matrix adhesion and epithelial-mesenchymal transition. Taken together, this study provides a novel molecular mechanism involving in the effects of GRP78 on colon cancer metastasis.CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved.

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.

Metastasis is the primary cause of death in lung cancer patients and EMT (epithelial-mesenchymal transition) promotes metastasis. Previous study revealed that DAL-1 (differentially expressed in adenocarcinoma of the lung) could attenuate EMT and metastasis in non-small cell lung cancer (NSCLC). Further study proved that HSPA5 (heat shock protein 5), which has a promoting effect on EMT, could bind to DAL-1. In this study, the mRNA and protein expression levels of target molecules were detected by RTq-PCR and western blot assays, the migration and invasion abilities were examined by Transwell migration and invasion assay, and the proliferation ability was measured by CCK-8 assay. We revealed that DAL-1 was downregulated while HSPA5 was upregulated in NSCLC and found the protein of DAL-1 and HSPA5 co-localized in the cytoplasm and nucleus. We demonstrated that DAL-1 can suppress the expression of HSPA5 on mRNA and protein levels, and decrease EMT, migration, invasion and proliferation abilities by down-regulating HSPA5. Furthermore, we discovered that DAL-1 plays a role in inhibiting PI3K/Akt/Mdm2 signaling pathway by suppressing HSPA5.