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Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

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Abstract

Background

Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT.

Methods

The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined.

Results

MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity.

Conclusion

This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.

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Acknowledgements

This work was supported by the Danish Cancer Society (R72-A4335-13-S2) to AJ. Additional funding for this project was obtained from the Nordea-fonden to LJR, the China Scholarship Council (CSC) to DL and the Research Fund at Rigshospitalet to JEN. The authors wish to thank the staff members at the Department of Pathology and Urology for help with collection of tissue. The excellent technical assistance of Camilla Tang Thomsen, Ana Ricci Nielsen, Brian Vendelbo Hansen and Betina F. Nielsen is gratefully acknowledged.

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  1. University Department of Growth and Reproduction (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen, Denmark

    Christiane Rudolph, Cecilie Melau, John E. Nielsen, Kristina Vile Jensen, Ewa Rajpert-De Meyts & Anne Jørgensen

  2. Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark

    Christiane Rudolph, Kristina Vile Jensen, Dekang Liu, Javier Pena-Diaz & Lene Juel Rasmussen

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  1. Christiane Rudolph
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Rudolph, C., Melau, C., Nielsen, J.E. et al. Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours. Cell Oncol. 40, 341–355 (2017). https://doi.org/10.1007/s13402-017-0326-8

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