title: SRY and OCT4 Are Required for the Acquisition of Cancer Stem Cell-Like Properties and Are Potential Differentiation Therapy Targets.
abstract: The acquisition of stemness is a hallmark of aggressive human hepatocellular carcinoma (hHCC). The stem cell marker OCT4 is frequently expressed in HCCs, and its expression correlates with those of putative cancer stem cell (CSC) markers and CSC properties. Here, we describe a novel mechanism of CSC maintenance by SRY through OCT4. We previously reported that Sry is involved in tumor malignancy in rodent HCCs. However, the oncogenic function of SRY in hHCCs is poorly understood. Ectopic expression of SRY increased multiple stem cell factors, including OCT4 and CD13. The OCT4 promoter contained SRY-binding sites that were directly activated by SRY. In HCC-derived cells, SRY knockdown decreased OCT4 expression and cancer stem-like phenotypes such as self-renewal, chemoresistance, and tumorigenicity. Conversely, OCT4 and SRY overexpression promoted cancer stem-like phenotypes. OCT4 knockdown in SRY clones downregulated the self-renewal capacity and chemoresistance. These data suggest that SRY is involved in the maintenance of cancer stem-like characteristics through OCT4. Moreover, CSCs of HCC-derived cells differentiated into Tuj1-positive neuron-like cells by retinoic acid. Noteworthily, SRY was highly expressed in some hHCC patients. Taken together, our findings imply a novel therapeutic strategy against CSCs of hHCCs.
authors.affiliation: Department of Biological Sciences and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Biological Sciences and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ninomiya
authors.affiliation: Department of Biological Sciences and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Sakamoto
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Biological Sciences and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
authors.forename: Hirotada
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Biological Sciences and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Tashiro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods; D055785:Gene Knockdown Techniques / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics; D051876:Sex-Determining Region Y Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein
keywords: Cancer stem cells; Hepatocellular carcinomas; OCT4; SRY