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Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer

Oncogene volume 32, pages 15–26 (2013)Cite this article

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Abstract

Epigenetic modifications are a driving force in carcinogenesis. However, their role in cancer metastasis remains poorly understood. The present study investigated the role of DNA methylation in the cervical cancer metastasis. Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with microarray analysis, we found that the protein tyrosine phosphatase receptor type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs. The methylation status of PTPRR increased in cervical scrapings (n=358) in accordance with disease severity, especially in invasive cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer.

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Acknowledgements

This work was supported by Grant NSC98-2314-B-016-030-MY3 from the National Science Council, Taiwan, ROC (to H-CL); Grant TSGH-C100-010-014-S01 (to M-HY) and TSGH-C100-010-014-S02 (H-CL) from the Tri-Service General Hospital and Teh-Tzer Study Group for Human Medical Research Foundation (to H-CL).

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Authors and Affiliations

  1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan

    P-H Su & H-C Lai

  2. Laboratory of Epigenetics and Cancer Stem Cells, National Defense Medical Center, Taipei, Taiwan

    P-H Su & H-C Lai

  3. Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan

    Y-W Lin

  4. Department of Obstetrics and Gynecology, Tri-Service General Hospital, Taipei, Taiwan

    R-L Huang, H-Y Lee, H-C Wang, M-H Yu & H-C Lai

  5. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    Y-P Liao, C-K Chen & H-C Lai

  6. Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan

    T-K Chao

  7. Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan

    M W Y Chan

  8. Department of Obstetrics and Gynecology, Tzu Chi University, Hualien, Taiwan

    T-Y Chu

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The patent of using PTPRR DNA methylation as a cancer biomarker is pending. The National Defense Medical Center owns the patent. H-C Lai is the inventor. All other authors declare no conflict of interest.

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Su, PH., Lin, YW., Huang, RL. et al. Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer. Oncogene 32, 15–26 (2013). https://doi.org/10.1038/onc.2012.29

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