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Abstract
Heat shock proteins (HSPs) are induced in response to extracellular stress and manage the quality of proteins as molecular chaperones. HSP70, a highly conserved HSP, has been reported to correlate with the proliferation and migration of human cancer cells, such as oral, prostate, lung and liver cancer. Regarding hepatocellular carcinoma (HCC), the HSP70 levels in the tumor tissues from patients are significantly higher than those in the normal liver tissues. HSP70 reportedly upregulates the migration and invasion of HCC. The AKT, p38 mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK) and Rho-kinase signaling pathways regulate the transforming growth factor (TGF)-α-induced migration of human HCC-derived HuH7 cells. However, the exact mechanism underlying the role of HSP70 in growth factor-induced HCC migration remains unclear. Therefore, in the present study, the mechanism underlying the involvement of HSP70 in TGF-α-induced HCC cell migration was investigated. Treatment with the HSP70 inhibitors VER155008 and YM-08 and the downregulation of HSP70 protein were confirmed to significantly suppress the TGF-α-induced cell migration of HuH7 cells. Both VER155008 and YM-08 reduced the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK, JNK or Rho-kinase. These results strongly suggest that HSP70 positively regulates the TGF-α-induced migration of HCC cells via the AKT signaling pathway.
Highlights
Heat shock proteins (HSPs) are a family of highly conserved proteins, and their expression is controlled to low levels in cells under normal conditions [1, 2, 3]
It has been reported that hepatocellular carcinoma (HCC) cell migration is induced by the upregulation of HSP70 expression [6], and HSP70 knockdown inhibits it [8]
The transforming growth factor (TGF)-α/epidermal growth factor receptor (EGFR) signaling pathway is well known to be involved in HCC development, including HCC cell migration [13, 16]
Summary
Heat shock proteins (HSPs) are a family of highly conserved proteins, and their expression is controlled to low levels in cells under normal conditions [1, 2, 3]. In response to environmental stresses, such as heat shock, hypoxia and nutrient starvation, the protein expression of HSPs is upregulated, and these molecules play a cytoprotective role as molecular chaperones by stabilizing correct protein folding and suppressing protein aggregation [1, 2, 3]. Since many oncoproteins require the high expression of HSP to maintain their function, the protein levels of HSPs are significantly higher in a wide range of cancer cells than in normal cells [3]. HSPs play a pivotal role in the progression of tumors and resistance against anti-cancer treatment and are currently considered therapeutic targets [1, 2, 3]
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