title: The Wnt/β-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells.
abstract: Hypoxia, a feature common to most solid tumors, is known to regulate many aspects of tumorigenesis. Recently, it was suggested that hypoxia increased the size of the cancer stem-cell (CSC) subpopulations and promoted the acquisition of a CSC-like phenotype. However, candidate hypoxia-regulated mediators specifically relevant to the stemness-related functions of colorectal CSCs have not been examined in detail. In the present study, we showed that hypoxia specifically promoted the self-renewal potential of CSCs. Through various in vitro studies, we found that hypoxia-induced Wnt/β-catenin signaling increased the occurrence of CSC-like phenotypes and the level of Id2 expression in colorectal-cancer cells. Importantly, the levels of hypoxia-induced CSC-sphere formation and Id2 expression were successfully attenuated by treatment with a Wnt/β-catenin-signaling inhibitor. We further demonstrated, for the first time, that the degree of hypoxia-induced CSC-sphere formation (CD44(+) subpopulation) in vitro and of tumor metastasis/dissemination in vivo were markedly suppressed by knocking down Id2 expression. Taken together, these data suggested that Wnt/β-catenin signaling mediated the hypoxia-induced self-renewal potential of colorectal-cancer CSCs through reactivating Id2 expression.
authors.affiliation: Laboratory of stem cell research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Dong
authors.affiliation: Laboratory of stem cell research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Gyu-Beom
authors.initials: GB
authors.lastname: Jang
authors.affiliation: The Faculty of Liberal Arts, Jungwon University, Chungbuk, 367-805, Republic of Korea.
authors.forename: Hwa-Yong
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Laboratory of stem cell research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Se-Ra
authors.initials: SR
authors.lastname: Park
authors.affiliation: Laboratory of stem cell research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.affiliation: Laboratory of stem cell research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.|Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Hong
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D051176:beta Catenin