title: An Atypical System for Studying Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma.
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.
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Dhiviya
authors.initials: D
authors.lastname: Vedagiri
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Hiren Vasantrai
authors.initials: HV
authors.lastname: Lashkari
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Abubakar Siddiq
authors.initials: AS
authors.lastname: Mangani
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Jedy
authors.initials: J
authors.lastname: Jose
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Avinash Raj
authors.initials: AR
authors.lastname: Thatipalli
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007 India.
authors.forename: Krishnan Harinivas
authors.initials: KH
authors.lastname: Harshan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D058750:Epithelial-Mesenchymal Transition; D005839:Gentamicins / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D005839:Gentamicins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014746:Vimentin; C010680:antibiotic G 418