Abstract
Intrahepatic and extrahepatic metastases are frequently detected in hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is believed to drive metastasis. There are not many well-established model systems to study EMT in HCC. Here we identified an atypical EMT while characterizing a population of mesenchymal cells in Huh7.5 hepatoma cell cultures. Cells with distinct morphology appeared during geneticin treatment of Huh7.5 cultures. Molecular characterization of geneticin resistant Huh7.5M cells confirmed EMT. Huh7.5M cells expressed cancer stem cell markers. p38MAPK and ERK1/2 were substantially activated in Huh7.5M cells. Their Inhibition elevated E-Cadherin expression with concerted suppression of Vimentin and anchorage independent growth in Huh7.5M cells. TGFβ could not induce EMT in Huh7.5 cultures, but enriched mesenchymal populations, similar to geneticin. Huh7.5M cells formed more aggressive solid tumors, primarily comprising cells with epithelial morphology, in nude mice. Canonical EMT-TFs did not participate in this atypical EMT, indicating that the established canonical EMT-TFs do not drive every EMT and there is a dire need to identify additional factors. The system that we characterized is a unique model to study EMT, MET and biphasic TGFβ signaling in HCC and offers considerable potential to facilitate more insightful studies on deeper questions in tumor metastasis.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most frequent malignant cancer worldwide and third most potent in cancer related mortality[1]
We serendipitously came across geneticin resistant (GR) colonies in Huh7.5 hepatoma cell culture treated with geneticin as high as 2 mg/ml
Epithelial mesenchymal transition (EMT) in cancer is a robust, dynamic process that prepares the cells to respond to various signals to facilitate its survival
Summary
Hepatocellular carcinoma (HCC) is the fifth most frequent malignant cancer worldwide and third most potent in cancer related mortality[1]. Hepatocytes generate extensive extracellular matrix (ECM) forming a sheath like basement membrane (BM) and have strong cell-cell adhesion They have distinct basal and apical polarity. EMT in carcinomas has been demonstrated to generate cells with stem cell like properties[8,9] and might be behind the generation of cancer stem cells (CSCs) Consistent with this theory, studies have identified circulating tumor cells (CTC) with EMT signatures[10]. EMT is facilitated through transcriptional reprogramming by members of Snail, Zeb and Twist family of transcription factors (EMT-TFs)[7,11] These transcriptional repressors target epithelial marker E-Cadherin[12], which is a major adhesion molecule in epithelial cells.
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