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Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1: the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer

Oncogene volume 35, pages 3577–3586 (2016)Cite this article

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Abstract

Fallopian tubal epithelium is a candidate for the origin of high-grade serous ovarian cancer. Transferrin-containing follicular fluid and/or retrograde menstrual blood are possible risk factors for carcinogenesis. Accumulation of DNA double-strand breaks (DNA-DSBs) in the fallopian tubal epithelium is considered to play an important role in the development of cancer. However, the mechanisms by which DNA-DSBs accumulate have not yet been fully elucidated. The hydroxyl radical, which is produced in a Fenton reaction catalyzed by an iron ion, serves as a potent DNA-DSB-inducing molecule, raising the potential of an iron ion transporter of transferrin in the formation of DNA-DSBs. We studied the potential involvement of transferrin in DNA damage and the development of ovarian cancer. Treatment with transferrin facilitated the formation of histone 2AX phosphorylated at Serine 139 (γH2AX), which is known as a DNA-DSB marker, in human fallopian tube secretory epithelial cells and A2780 ovarian cancer cells. Knockdown of transferrin receptor 1 (TfR1), but not transferrin receptor 2, suppressed the transferrin uptake and consequent formation of γH2AX. As hydroxyl radicals in reactive oxygen species (ROS) are involved in DNA-DSBs, the formation of ROS was determined. Treatment with TfR1-specific small interference RNAs significantly diminished transferrin-induced formation of ROS. Moreover, TfR1-dependent uptake of transferrin was revealed to augment the formation of DNA-DSBs in the presence of hydrogen peroxide, which served as a substrate for the Fenton reaction. An ex vivo study with murine fallopian tubes further demonstrated that transferrin treatment introduced DNA-DSBs in the fallopian tubal epithelium. Collectively, these data suggested that the transferrin-TfR1 axis accounts for the induction of DNA-DSBs that potentially lead to DNA damage/genome instability. These findings also suggested that exposure to transferrin initiates and promotes the development of ovarian cancer by aiding the accumulation of DNA-DSBs in the fallopian tubal epithelium.

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Acknowledgements

We thank Drs Ronny Drapkin and Alison M Karst for kindly providing FTSECs established in their laboratory. This study was supported in part by the JSPS KAKENHI Grants (23791801 and 26462509 to MT, 23790366, 26861304 and 40539235 to KK, 24390375 and 26670710 to NY), a Health Labor Sciences Research Grant (201221019A to NY), the Kurokawa Cancer Research Foundation (MT), the Japan Society of Gynecologic Oncology (MT), the Foundation for Promotion of Cancer Research (MT) and Tohoku University Graduate School of Medicine United Center for Advanced Research and Translational Medicine (MT).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan

    S Shigeta, M Toyoshima, K Kitatani, M Ishibashi & N Yaegashi

  2. Department of Obstetrics and Gynecology, Sendai Medical Center, Sendai, Japan

    M Toyoshima

  3. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    K Kitatani & T Usui

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Shigeta, S., Toyoshima, M., Kitatani, K. et al. Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1: the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer. Oncogene 35, 3577–3586 (2016). https://doi.org/10.1038/onc.2015.425

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