title: Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer.
abstract: CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yung-Sheng
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Hsu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Meng-Chi
authors.initials: MC
authors.lastname: Yen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hau-Lun
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tzu-Yang
authors.initials: TY
authors.lastname: Weng
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Lai
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yih-Jyh
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center for Infectious Diseases and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
mesh_terms: D000071916:AC133 Antigen; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D010455:Peptides / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D018800:Thy-1 Antigens / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D016023:Integrins; C583117:OSU-CG5; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D018800:Thy-1 Antigens; D055372:AMP-Activated Protein Kinases
keywords: AMPK; OSU-CG5; cancer stem cell marker; integrin; mTOR