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) Radiofrequency ablation (RFA) is Silmitasertib molecular weight accepted as a potentially curative therapy for the early stages of primary hepatocellular carcinoma (HCC).[1] RFA induces tumor necrosis with low complication rates and is superior to percutaneous ethanol injection in tumor Selleck PLX4032 ablation.[2] However, suboptimal RFA treatment for HCC has been reported as a risk factor of early diffuse recurrence.[3] Large tumor size is a major risk factor of local recurrence because of poorly defined margins.[4] Such recurrent HCC appears to behave more aggressively

than before RFA[5-8] and significantly reduces overall survival (OS) of HCC patients.[9] Phenotypic and functional alterations of HCC cells subjected to heat treatment have not been studied. Epithelial-mesenchymal transition (EMT) is thought to be a critical factor in progression of cancer and dictating metastasis. Several oncogenic pathways (such as those of growth and transcription factors, integrins, Wnt/β-catenin, and Notch) can induce EMT.[10] In particular, the Ras/extracellular signal-related kinase (Erk)1/2 pathway has been shown to activate two EMT-related transcription factors, else namely, Snail and Slug.[11] A recent clinical study has shown a correlation of Snail transcript levels with

capsular and portal invasion of HCC.[12] Other inducers of EMT in HCC are TWIST1 and CHD1L.[13, 14] Moreover, expression of type I procollagen (COL1A1) is a useful marker of transition to a mesenchymal phenotype.[15] Src homology and collagen (Shc) is a central SH2-containing cytoplasmic adaptor protein, which directly binds to tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor beta (PDGFRβ), insulin-like growth factor 1 receptor (IGF-1R), and fibroblast growth factor receptor (FGFR). Notably, Shc is a central player in malignant transformation.[16-20] Mitogenic, transforming, and proinvasive signal transduction from Shc to mitogen-activated protein kinases (MAPKs) by Grb2-Sos has been well studied,[21-23] with p46-Shc and p52-Shc being central upstream regulators of MAPK activation, whereas the alternatively spliced p66-Shc isoform appears to promote apoptosis.