title: Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer.
abstract: Most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs). Tumor-selective replication of oncolytic adenoviruses may be hindered by oxygen deprivation in tumors. It is desirable to develop a potent oncolytic adenovirus, retaining its antitumor activity even in a hypoxic environment. We have previously generated an Oct4-dependent oncolytic adenovirus, namely Ad9OC, driven by nine copies of the Oct4 response element (ORE) for specifically killing Oct4-overexpressing bladder tumors. Here, we developed a novel Oct4 and hypoxia dual-regulated oncolytic adenovirus, designated AdLCY, driven by both hypoxia response element (HRE) and ORE. We showed that hypoxia-inducible factor (HIF)-2α and Oct4 were frequently overexpressed in hypoxic bladder cancer cells, and HIF-2α was involved in HRE-dependent and Oct4 transactivation. AdLCY exhibited higher cytolytic activities than Ad9OC against hypoxic bladder cancer cells, while sparing normal cells. AdLCY exerted potent antitumor effects in mice bearing human bladder tumor xenografts and syngeneic bladder tumors. It could target hypoxic CD44- and CD133-positive bladder tumor cells. Therefore, AdLCY may have therapeutic potential for targeting hypoxic bladder tumors and CSCs. As Oct4 is expressed in various cancers, AdLCY may be further explored as a broad-spectrum anticancer agent.
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: C-S
authors.initials: CS
authors.lastname: Lu
authors.affiliation: Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan.
authors.forename: J-L
authors.initials: JL
authors.lastname: Hsieh
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: H-W
authors.initials: HW
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: B-H
authors.initials: BH
authors.lastname: Su
authors.affiliation: Department of Urology, Tainan Hospital, Department of Health, Executive Yuan, Tainan, Taiwan.
authors.forename: G-S
authors.initials: GS
authors.lastname: Shieh
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Su
authors.affiliation: Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: A-L
authors.initials: AL
authors.lastname: Shiau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D050504:Oncolytic Viruses / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D050814:Octamer Transcription Factor-3; D000099162:Endothelial PAS Domain-Containing Protein 1; C494173:POU5F1 protein, human