title: Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer.
abstract: To study the mechanisms of gastric tumorigenesis, we have established CSN cell line from human normal gastric mucosa, and CS12, a tumorigenic and invasive gastric cancer cell line from CSN passages. Many stem cell markers were expressed in both CSN and CS12 cells, but LGR5 and NANOG were expressed only in CS12 cells. Increased expression of homeobox A13 (HoxA13) and its downstream cascades was significant for the tumorigenic activity of CS12 cells, and was associated with recruitment of E2F-1 to HoxA13 promoter accompanied with increased trimethylation of histone H3 lysine 4 (H3K4me3) at the hypomethylated E2F motifs. Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. Concurrent regulation of HoxA13-HOTTIP was mediated by the mixed lineage leukemia-WD repeat domain 5 complex, which caused the trimethylation of H3K4 and then stimulated cell proliferation. HoxA13 transactivated the IGFBP-3 promoter through the HOX-binding site. Activation of IGFBP-3 stimulated the oncogenic potential and invasion activity. Increased expression of HoxA13 (63.2%) and IGFBP-3 (28.6%) was detected in human gastric cancer tissues and was found in the gastric cancer data of The Cancer Genome Atlas. Taken together, the HoxA13-HOTTIP-IGFBP-3 cascade is critical for the carcinogenic characteristics of CS12 cells.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Sophie Sw
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Kenly
authors.initials: K
authors.lastname: Wuputra
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Yin-Chu
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Chen-Lung Steve
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Ming-Ho
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Shin-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Ker-Kong
authors.initials: KK
authors.lastname: Chen
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: Cell Engineering Division, BioResource Center, RIKEN, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: School of Science and Engineering, Teikyo University, Utsunomia, Tochigi 329-2192, Japan.|Saito Laboratory of Cell Technology, Yaita, Tochigi 329-2192, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Saito
authors.affiliation: Advanced Science Research Center, Okayama University, Okayama, Okayama 700-8558, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hanafusa
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 807, Taiwan.|Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
authors.forename: Chang-Shen
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Center for Stem Cell Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Center of 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: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D016513:Mice, SCID; D009857:Oncogenes / Q000235:genetics; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D062085:RNA, Long Noncoding; C099959:homeobox protein HOXA13; C000613830:long noncoding RNA HOTTIP, human
keywords: HOTTIP; HoxA13; IGFBP-3; gastric cancer cells; p53-E2F signaling