title: Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC.
abstract: Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is involved in cell proliferation and progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms linking gene expression and tumor formation remain unclear. In this study, we found that ISX transcriptionally activated E2F transcription factor 1 (E2F1) and associated oncogenic activity by directly binding to the E2 site of its promoter. Forced expression of ISX increased the expression of and phosphorylated the serine residue at position 332 of E2F1, which may be translocated into the nucleus to form the E2F1-DP-1 complex, suggesting that the promotion of oncogenic activities of the ISX-E2F1 axis plays a critical role in hepatoma cells. Coexpression of ISX and E2F1 significantly promoted p53 and RB-mediated cell proliferation and anti-apoptosis, and repressed apoptosis and autophagy. In contrast, short hairpin RNAi-mediated attenuation of ISX and E2F1 decreased cell proliferation and malignant transformation, respectively, in hepatoma cells in vitro and in vivo. The mRNA expression of E2F1 and ISX in 238 paired specimens from human HCC patients, and the adjacent, normal tissues exhibited a tumor-specific expression pattern which was highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. Therefore, our results indicate that E2F1 is an important downstream gene of ISX in hepatoma progression.
authors.affiliation: Division of Hepatobiliary Surgery, Department of Surgery, Faculty of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shen-Nien
authors.initials: SN
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Wang
authors.affiliation: Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan.|Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Ding-Ping
authors.initials: DP
authors.lastname: Sun
authors.affiliation: Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Edward
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Department of Internal Medicine, Division of Hepatogastroenterology, Chi-Mei Medical Center, Tainan, Taiwan.|Department of Senior Citizen Service Management, Chia Nan University of Pharmacy & Science, Tainan, Taiwan.
authors.forename: Hsing-Tao
authors.initials: HT
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Research Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Faculty of Science and Engineering, Tokushima Bunri University, Sanuki, Japan.|Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shih-Hsien
authors.initials: SH
authors.lastname: Hsu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D018398:Homeodomain Proteins; C579132:Isx protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors
keywords: DP1; E2F1; ISX; cyclin D1; hepatocellular carcinoma (HCC)