title: Transcriptional regulation of the alpha-1 type II collagen gene by nuclear factor B/p65 and Sox9 in the chondrocytic phenotype of uterine carcinosarcomas.
abstract: Uterine carcinosarcomas (U-CSs) are considered monoclonal in origin, but little is known about the mechanisms for establishment of heterologous sarcomatous components. Here, we examine the functional roles of nuclear factor κB (NF-κB)/p65 and Sox9 in the transcriptional regulation of alpha-1 type II collagen (COL2A1), a hallmark of chondrogenesis, during morphologic change in the direction of the chondrocytic phenotype. In 32 cases of U-CS, both phosphorylated p65 and Sox9 expression were colocalized in Col2A1-positive sarcomatous components, particularly in cartilaginous elements, with strongly positive correlation (ρ = 0.72, P = .005). A positive association of Col2A1 expression between protein (immunohistochemistry) and messenger RNA (in situ hybridization) assays was evident in sarcomatous components, whereas 9 cases also showed distinct positive signals for the messenger RNA without protein expression in carcinomatous elements, probably through a posttranscriptional and/or posttranslational modulation mechanism. In the Ishikawa endometrial cancer line, overexpression of p65 could activate transcription of COL2A1 promoter-intron reporters through binding to specific NF-κB sites in the first intron, along with up-regulation of Sox9. Exogenous induction of Sox9 also caused an increase in transcription of COL2A1, in contrast to a repression of the p65-mediated COL2A1 transcription, suggesting the existence of a negative feedback loop. These data, therefore, suggest that NF-κB/p65 signaling, as well as Sox9, may contribute to changes in the morphology of U-CS cells toward the chondrocytic phenotype through modulation of COL2A1 transcription.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshida
authors.forename: Miki
authors.initials: M
authors.lastname: Hashimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.forename: Toshihide
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Erina
authors.initials: E
authors.lastname: Suzuki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tazo
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakajima
authors.forename: Madoka
authors.initials: M
authors.lastname: Inukai
authors.forename: Makoto
authors.initials: M
authors.lastname: Saegusa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002296:Carcinosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D024043:Collagen Type II / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D008875:Middle Aged; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II; D004273:DNA, Neoplasm; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D051996:Transcription Factor RelA
keywords: Clo2A1; NF-κB; Sox9; Uterine carcinosarcoma