Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma.

Yoshida S, Kornek M, Ikenaga N, Schmelzle M, Masuzaki R, Csizmadia E, Wu Y, Robson SC, Schuppan D
Hepatology. 2013 58 (5): 1667-80

PMID: 23729316 · DOI:10.1002/hep.26526

UNLABELLED - 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°C-55°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°C killed all HCC cells, whereas 65%-85% of cells survived 48°C-50°C, developing spindle-like morphology and expressing CD133, cytokeratin (CK)7, CK19, procollagen-α1(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.

© 2013 by the American Association for the Study of Liver Diseases.

MeSH Terms (21)

Adult Aged Animals Carcinoma, Hepatocellular Catheter Ablation Cell Proliferation Cell Survival Epithelial-Mesenchymal Transition Extracellular Signal-Regulated MAP Kinases Female Heat-Shock Proteins Hep G2 Cells Humans Liver Neoplasms Male Mice Mice, Inbred BALB C Middle Aged Phosphorylation Shc Signaling Adaptor Proteins Src Homology 2 Domain-Containing, Transforming Protein 1

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