title: Genetic screen identifies suppressor of morphogenesis in genitalia-1 (SMG-1) as a modulator of sorafenib resistance in hepatocellular carcinoma cell lines.
abstract: Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis and a very complex dysregulated molecular etiology. Furthermore, conventional therapy thus far has had only limited success. A recently developed oral multikinase inhibitor, sorafenib, has been used to improve survival in HCC patients, however, follow‑up studies have revealed a high rate of cancer recurrence. Therefore, identification of genes involved in sorafenib resistance is urgently required. RNA interference (RNAi) is a powerful tool for performing loss-of-function genetic screens and can facilitate the identification of components of the cellular signaling pathway. This study describes the results of an unbiased genomic screening using RNAi in an HCC cell line to elucidate genes related to sorafenib non-responsiveness or resistance. A genome-wide in vitro RNA interference screen revealed the role of suppressor of morphogenesis in genitalia-1 (SMG-1) as a determinant of sorafenib resistance. The inhibition of SMG-1 reduced sorafenib sensitivity in the studied HCC cell lines. An immunohistochemical comparison of cancerous and non‑cancerous regions showed strong staining in the non‑neoplastic hepatocyte regions of HCC. SMG-1 may warrant investigation as an agent to reverse sorafenib resistance.
authors.affiliation: Hepatobiliary Unit, Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, Medical School of the Catholic University of Korea, Incheon, Republic of Korea.
authors.forename: Soon Woo
authors.initials: SW
authors.lastname: Nam
authors.affiliation: Clinical Medicine Research Institute, Daejeon St. Mary's Hospital, Daejeon, Republic of Korea.
authors.forename: Ki Cheol
authors.initials: KC
authors.lastname: Park
authors.affiliation: Clinical Medicine Research Institute, Daejeon St. Mary's Hospital, Daejeon, Republic of Korea.
authors.forename: Keum Jin
authors.initials: KJ
authors.lastname: Yang
authors.affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology, University of Calgary, AB, Canada.
authors.forename: Byoungchun
authors.initials: B
authors.lastname: Lee
authors.affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology, University of Calgary, AB, Canada.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015894:Genome, Human; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000077157:Sorafenib; C514704:SMG1 protein, human