Journal
HEPATOLOGY
Volume 58, Issue 5, Pages 1667-1680Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.26526
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [1 R21 DK075857-01A2, U19 AI066313-05]
- German Research Foundation (DFG) [KO4103/1-1]
- American Liver Foundation
- DFG [SCHM 2661/1-1, 2661/1-2]
- German Federal Ministry of Education and Research (BMBF) [0315883]
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Radiofrequency ablation (RFA) is a potentially curative therapy for hepatocellular carcinoma (HCC). However, incomplete RFA can induce accelerated invasive growth at the periphery. The mechanisms underlying the RFA-induced tumor promotion remain largely unexplored. Three human HCC cell lines were exposed to 45 degrees C-55 degrees C for 10 minutes, simulating the marginal zone of RFA treatment. At 5-12 days post-treatment cell proliferation, parameters of epithelial-mesenchymal transition (EMT), and activation of mitogen-activated protein kinases were analyzed. Livers from patients with viral hepatitis without and with HCC (n=114) were examined to confirm the relevance of altered kinase patterns. In vivo tumorigenic potential of heat-treated versus untreated HCC cells was studied in nude mice. Heating to 55 degrees C killed all HCC cells, whereas 65%-85% of cells survived 48 degrees C-50 degrees C, developing spindle-like morphology and expressing CD133, cytokeratin (CK)7, CK19, procollagen-1(I), and Snail at day 5 after heat exposure, which returned to baseline at day 12. Heat-exposed HCC cells showed enhanced proliferation and prominent activation of p46-Shc (Src homology and collagen) and downstream extracellular signal-related kinase (Erk)1/2. In patients, Shc expression correlated with malignant potential and overall survival. Blocking Erk1/2 reduced proliferation and EMT-like changes of heat-treated HCC cells. Implantation of heat-exposed HEPG2 cells into nude mice induced significantly larger, more aggressive tumors than untreated cells. Conclusions: Sublethal heat treatment skews HCC cells toward EMT and transforms them to a progenitor-like, highly proliferative cellular phenotype in vitro and in vivo, which is driven significantly by p46Shc-Erk1/2. Suboptimal RFA accelerates HCC growth and spread by transiently inducing an EMT-like, more aggressive cellular phenotype. (Hepatology 2013;58:1667-1680)
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