title: A population of BJ fibroblasts escaped from Ras-induced senescence susceptible to transformation.
abstract: Oncogenic stimuli such as H-Ras induce oncogene-induced senescence (OIS) in fibroblasts to protect against transformation. Here we found that a population of the human diploid fibroblasts can escape from OIS induced by H-RasV12. We designated these OIS-escaped cells as OISEC (OIS-escaped cells). OISEC lost the expression of p16 which plays an important role for cell cycle arrest for induction of senescence, but OISEC preserved the p16 expression machinery and exhibited senescence by the treatment with hydrogen peroxide (H(2)O(2)) as stress-induced premature senescence (SIPS). OISEC did not possess anchorage-independent growth potential, and functional disruption of p53 and Rb by SV40 early region encoding large T and small t antigens, induced the aneuploidy phenotype and colony-forming potential of OISEC together with the exhibition of in vivo tumor formation. Finally, we also found that the distinctive feature of OISEC is expression of transcription factors, Oct3/4, SOX2, and Nanog which is closely related to stem-like cell features. This study highlights the presence of a cell population which escaped from OIS, and this OISEC may transform into malignant cancer cells by the additional hits of several genes in vivo.
authors.affiliation: Laboratory of Cancer Research, Department of Pathology, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kohsaka
authors.forename: Ken
authors.initials: K
authors.lastname: Sasai
authors.forename: Kenta
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Akagi
authors.forename: Mishie
authors.initials: M
authors.lastname: Tanino
authors.forename: Taichi
authors.initials: T
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004171:Diploidy; D005347:Fibroblasts / Q000473:pathology*; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16