Expression and function role of DNA methyltransferase 1 in human bladder cancer

Authors

  • Chun-Te Wu MD, PhD,

    1. Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan
    2. Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan
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  • Ching-Fang Wu MD, PhD,

    1. Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan
    2. Department of Urology, Chang Gung Memorial Hospital, Chiayi, Taiwan
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  • Chang-Hsien Lu MD,

    1. Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan
    2. Department of Hematology, Chang Gung Memorial Hospital, Chiayi, Taiwan
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  • Cheng-Chia Lin MD,

    1. Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan
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  • Wen-Cheng Chen MD,

    1. Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan
    2. Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan
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  • Paul-Yang Lin MD,

    1. Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan
    2. Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan
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  • Miao-Fen Chen MD, PhD

    Corresponding author
    1. Chang Gung University College of Medicine and Chang Gung Institute of Technology, Taiwan
    2. Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan
    • Department of Radiation Oncology, Chang-Gung Memorial Hospital at Chiayi, #6, Chia-Pu Road, Putz City, Chia-Yi Hsien, Taiwan
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    • Fax: (011) 886-5-3623002


Abstract

BACKGROUND:

The identification of potential tumor markers will help improve therapeutic planning and patient management. Therefore, the aim of this study was to highlight the role of DNA methyltransferase 1 (DNMT1) in bladder cancer.

METHODS:

A total of 50 samples of nonmalignant urothelium, 65 of muscle-invasive bladder cancers, 15 of distant metastasis, and 50 of nonmuscle-invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments investigating changes in tumor behavior, treatment response, and related signaling in bladder cancer.

RESULTS:

The incidence of nuclear DNMT1 immunoreactivity in the bladder cancer specimens (45%) was significantly higher than in nonmalignant urothelium (15%, P = .0005), and the incidence in cancer was positively linked to clinical stage (24% in ≤T1 vs 55% in T2-T4, P = .0007). The staining of DNMT1 was also significantly linked to lower complete response rates (P = .0014) and reduced survival rates (P = .000). By in vitro and in vivo experiments, DNMT1 silencing vector reduced tumor growth and attenuated treatment resistance in bladder cancer cells. Less epithelial-mesenchymal transition, less invasion, and slower tumor growth were noted in cancer cells with inhibited DNMT1. Furthermore, the epidermal growth factor receptor-mediated phosphatidylinositol 3′–kinase-protein kinase B pathway might be the mechanism underlying the effects of DNMT1 on bladder cancer.

CONCLUSIONS:

DNMT1 could be a significant clinical predictor for stage and treatment response of bladder cancer. Moreover, targeting this enzyme could be a promising strategy for treating bladder cancer, as evidenced by inhibited tumor growth and enhanced radiosensitivity. Cancer 2011;. © 2011 American Cancer Society.

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