Disruption of the p53-p53r2 DNA repair system in ulcerative colitis contributes to colon tumorigenesis.
With ulcerative colitis (UC)-associated tumorigenesis, p53 gene alteration is considered to be a key event. To clarify whether the p53-checkpoint is operating in foci of inflammation and that its disruption is a feature of UC-associated neoplasms, the present immunohistochemical study was conducted. Since accumulation of butyric acid with active UC is associated with apoptosis, effects of in vitro exposure of newly established UC-cancer derived cell lines to organic acids were also assessed. The regulatory subunit of ribonucleotide reductase, p53R2, was found to be localized with p53 in situ, and levels of p53, phospho-p53, p53R2 and inducible nitric oxide synthase were significantly intercorrelated. However, p53R2 expression was clearly reduced with progression through UC-associated dysplasia to carcinoma, demonstrating an inverse relation with p53 overexpression. In vitro treatment with butyrate or propionic acid, but not succinic acid, elicited a positive response in the p53-p53R2 system. Moreover, p53-dependent DNA repair, investigated by radioactive nucleotide incorporation, was induced by butyric acid and inhibited by short-interfering p53 and p53R2 RNAs. Therefore, it was concluded that the p53-p53R2-dependent DNA repair system is constitutively stimulated by butyric acid, which accumulates in UC inflammatory lesions. Since failure of the p53-G(1) checkpoint may cause dysfunction of repair under the influence of butyrate, gene alterations may increase and spread through the genome, leading to tumorigenesis.
Yoshida
Tsutomu
T
Department of Pathology, Kitasato University School of Medicine, Kitasato, Sagamihara, Kanagawa, Japan. tyoshida@med.kitasato-u.ac.jp
Haga
Shiori
S
Numata
Yoshiko
Y
Yamashita
Kazuya
K
Mikami
Tetuo
T
Ogawa
Taishi
T
Ohkusa
Toshifumi
T
Okayasu
Isao
I
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004260:DNA Repair; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D019802:Succinic Acid / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D002087:Butyrates; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019802:Succinic Acid; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases