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Sublethal heat treatment promotes epithelial‐mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma
Author(s) -
Yoshida Shuhei,
Kornek Miroslaw,
Ikenaga Naoki,
Schmelzle Moritz,
Masuzaki Ryota,
Csizmadia Eva,
Wu Yan,
Robson Simon C.,
Schuppan Detlef
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26526
Subject(s) - epithelial–mesenchymal transition , hepatocellular carcinoma , cancer research , mapk/erk pathway , progenitor cell , kinase , medicine , cytokeratin , cell growth , pathology , chemistry , biology , stem cell , metastasis , cancer , microbiology and biotechnology , immunohistochemistry , biochemistry
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. (H epatology 2013;58:1667–1680)