title: Involvement of p53 mutation and mismatch repair proteins dysregulation in NNK-induced malignant transformation of human bronchial epithelial cells.
abstract: Genome integrity is essential for normal cellular functions and cell survival. Its instability can cause genetic aberrations and is considered as a hallmark of most cancers. To investigate the carcinogenesis process induced by tobacco-specific carcinogen NNK, we studied the dynamic changes of two important protectors of genome integrity, p53 and MMR system, in malignant transformation of human bronchial epithelial cells after NNK exposure. Our results showed that the expression of MLH1, one of the important MMR proteins, was decreased early and maintained the downregulation during the transformation in a histone modification involved and DNA methylation-independent manner. Another MMR protein PMS2 also displayed a declined expression while being in a later stage of transformation. Moreover, we conducted p53 mutation analysis and revealed a mutation at codon 273 which led to the replacement of arginine by histidine. With the mutation, DNA damage-induced activation of p53 was significantly impaired. We further reintroduced the wild-type p53 into the transformed cells, and the malignant proliferation can be abrogated by inducing cell cycle arrest and apoptosis. These findings indicate that p53 and MMR system play an important role in the initiation and progression of NNK-induced transformation, and p53 could be a potential therapeutic target for tobacco-related cancers.
authors.affiliation: Department of Clinical Medicine, Zhejiang Medical College, Hangzhou 310053, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Shuilian
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pulmonology, Sir Run Run Shaw Hospital, Hangzhou 310016, China.
authors.forename: Zhengyang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000251:Adenosine Triphosphatases / Q000096:biosynthesis*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics; D045643:DNA Repair Enzymes / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D042822:Genomic Instability / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D009602:Nitrosamines / Q000633:toxicity; D009687:Nuclear Proteins / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009602:Nitrosamines; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes