Abstract
The aims of the current study were to investigate the influence of insufficient radiofrequency ablation (RFA) on the cell proliferation of the human hepatocellular carcinoma (HCC) cells, SMMC7721, and to elucidate the underlying mechanism. SMMC7721 cells were subjected to a 47°C treatment regimen to simulate insufficient RFA, in the presence or absence of KN93 [a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII)], PD98059 [a specific inhibitor of extracellular signal-regulated kinase (ERK)], or axitinib (a specific inhibitor of vascular endothelial growth factor (VEGF) receptor]. Cell proliferation was determined using a thiazolyl terazolium assay (MTT). The levels of CaMKII, phospho-CaMKII, ERK, phospho-ERK and VEGF were observed by western blot analysis. The results demonstrated that the 47°C treatment regimen: i) Triggered upregulation of VEGF expression in the SMMC7721 cells, which was reduced by CaMKII or ERK inhibition; ii) induced ERK activation was prevented by KN93; and iii) promoted SMMC7721 cell proliferation, which was greatly inhibited by axitinib, KN93 and PD98059. In conclusion, the results indicated that insufficient RFA promotes SMMC7721 cell proliferation by activating CaMKII/ERK-dependent VEGF overexpression.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and a major public health problemAngiogenesis is one of the critical mechanisms involved in the proliferation and growth of tumor cells [10]
To investigate the effect of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), extracellular signal‐regulated kinase (ERK) and vascular endothelial growth factor (VEGF) on the growth of residual SMMC7721 cells in the 47 ̊C treatment group, 10 μM KN93, a specific CaMKII inhibitor, 20 μM PD98059, a specific ERK inhibitor, or 5 μM axitinib, a VEGF receptor antagonist
VEGF overexpression is triggered by 47 ̊C heat treatment and blocked by ERK and CaMKII
Summary
Angiogenesis is one of the critical mechanisms involved in the proliferation and growth of tumor cells [10]. Among the numerous angiogenesis‐associated genes, vascular endothelial growth factor (VEGF) functions as a potent angiogenic factor and is ubiquitously expressed in various types of cancer, including HCC [9,11]. A previous study has demonstrated that VEGF overexpression in HCC is typically associated with tumor progression, reduced median survival and recurrence following treatment [12]. A recent study has identified that insufficient RFA induced the aggressive growth of residual HCC mediated by VEGF overexpression [9]. The underlying mechanisms by which insufficient RFA enhances VEGF expression remain unknown. The aim of the present study was to investigate the mechanisms by which insufficient RFA promotes HCC proliferation, the intracellular signaling pathway(s) involved in VEGF overexpression
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