title: Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related deaths worldwide. Limitations in HCC treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only FDA approved drug available for advanced HCC patients, and development of second-line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib-resistant cells from Huh7 and Mahlavu cell lines by long-term sorafenib exposure. Sorafenib-resistant HCC cells acquired spindle-shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long-term sorafenib treatment, HCC cells showed induction of hepatocyte growth factor (HGF) synthesis and secretion along with increased levels of c-Met kinase and its active phosphorylated form, indicating autocrine activation of HGF/c-Met signaling. Importantly, the combined treatment of the resistant cells with c-Met kinase inhibitor SU11274 and HGF neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib-induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of HGF synthesis leading to autocrine activation of HGF/c-Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with HGF and c-Met inhibitors comprise promising candidates for overcoming sorafenib resistance.
authors.affiliation: Faculty of Engineering and Computer Science, Izmir University of Economics, Izmir.|Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Firtina Karagonlar
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.
authors.forename: Dogukan
authors.initials: D
authors.lastname: Koc
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.
authors.forename: Evin
authors.initials: E
authors.lastname: Iscan
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.|Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Erdal
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.|Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Neşe
authors.initials: N
authors.lastname: Atabey
mesh_terms: D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D057134:Antibodies, Neutralizing; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D013449:Sulfonamides; D009536:Niacinamide; D017228:Hepatocyte Growth Factor; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met
keywords: c-Met; hepatocarcinogenesis; hepatocyte growth factor; liver cancer; sorafenib