title: Hypoxia and TP53 deficiency for induced pluripotent stem cell-like properties             in gastrointestinal cancer.
abstract: Induced pluripotent stem (iPS)-like cancer cells (iPC) by the introduction             of defined transcription factors reduce the prevalence of the malignant phenotype             of digestive system cancer cells, but the induction efficiency is low. The role             of hypoxia and TP53 deficiency in iPC cell generation remain unclear. Cellular             reprogramming was performed by retroviral infection with OCT3/4, SOX2, KLF4 and             c-MYC of wild-type HCT116 colorectal cancer cells and mutant TP53-deficient HCT116             cells. Cells were cultured in normoxia (21% O2) or hypoxia (5% O2) for 30 days             after transduction, and the response to hypoxia and comparison of cellular proliferation,             invasion and tumourigenesis before and after iPC cell generation were studied.             iPC cell generation from wild-type HCT116 cells in hypoxia was approximately 4-times             greater than in normoxia (p<0.05), and TP53 deficiency increased conversion             efficiency significantly in normoxia (p<0.05). Significant involvement of hypoxia-inducible             factors was observed in an immature carbohydrate epitope, Tra-1-60+, colony formation.             Generated iPC cells exhibited multi-differentiation potential. Although the iPC             cells in hypoxia exhibited reduced proliferation, invasiveness and tumourigenicity,             TP53 deficiency in iPC cells resulted in higher tumourigenicity than in wild-type             cells. Both hypoxia and TP53 deficiency increase iPC cell generation. TP53 deficiency             can also result in deleterious mutations, whereas hypoxia may impact molecular             targets of epigenome normalisation.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate                     School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hoshino
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Haraguchi
authors.forename: Shimpei
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Akira
authors.initials: A
authors.lastname: Tomokuni
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kano
authors.forename: Takahito
authors.initials: T
authors.lastname: Fukusumi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Saito
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ozaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sakai
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Sekimoto
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D045325:HCT116 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012190:Retroviridae / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53