title: Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer.
abstract: The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613-2624.
authors.affiliation: Department of Surgery.|Center of Stem Cell Research.
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.affiliation: Department of Surgery.
authors.forename: King-Teh
authors.initials: KT
authors.lastname: Lee
authors.affiliation: School of Dentistry.
authors.forename: Ker-Kong
authors.initials: KK
authors.lastname: Chen
authors.affiliation: Department of Surgery.|Graduate Institute of Medicine.|Center of Stem Cell Research.
authors.forename: Ya-Han
authors.initials: YH
authors.lastname: Yang
authors.affiliation: School of Dentistry.
authors.forename: Ying-Chu
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medicine.
authors.forename: Ming-Ho
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medicine.
authors.forename: Kenly
authors.initials: K
authors.lastname: Wuputra
authors.affiliation: Welgene Biotech. Inc, Taipei, Taiwan.
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medicine.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Ku
authors.affiliation: Department of Physiology, Keio University School of Medicine, Shinanomachi, Tokyo, 160-8582, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: RIKEN BioResource Center, Tsukuba, 305-0074, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Saito Laboratory of Cell Technology, Yaita, Tochigi, 329-1571, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Pathology.
authors.forename: Chun-Chieh
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Pathology.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Eckner
authors.affiliation: Department of Surgery.|Graduate Institute of Medicine.
authors.forename: Chen-Lung
authors.initials: CL
authors.lastname: Steve Lin
authors.affiliation: Department of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.|Center of Stem Cell Research.
authors.forename: Sophie S-W
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.|Center of Stem Cell Research.|Center of Infectious Diseases and Cancer Research.|Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, 807, Taiwan.
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medicine.|Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan.
authors.forename: Chang-Shen
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medicine.|Center of Stem Cell Research.|Center of Infectious Diseases and Cancer Research.|Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.|Faculty of Science and Engineering, Tokushima Bunri University, Sanuki, 763-2193, Japan.|Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D025461:Feedback, Physiological; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D002945:Cisplatin; D005472:Fluorouracil
keywords: Cancer stem cells; Liver cancer; OCT4; Pluripotency; Positive feedback; Reprogramming; c-JUN