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Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers

Oncogene volume 23, pages 1117–1124 (2004)Cite this article

Abstract

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but the biological significance of DNA hypomethylation in carcinogenesis is less understood. The expression of Maspin (mammary serpin) in differentiated normal cells is regulated by epigenetic modifications in a cell-type-specific manner. Paradoxical Maspin expression due to epigenetic modification has been addressed in several cancer cell types. To elucidate the role of the Maspin gene in thyroid cancer, we studied methylation status in the promoter region and its expression in six human undifferentiated thyroid cancer cell lines and in specimens from 92 primary thyroid tumors, consisting of six follicular adenomas, 56 well-differentiated thyroid cancers (WDTCs), 17 poorly differentiated thyroid cancers (PDTCs) and 13 undifferentiated thyroid cancers (UDTCs). Three of the six cell lines overexpressed Maspin mRNA and its protein product, but the remaining three did not. The methylation status at the promoter region was inversely correlated with Maspin expression. In Maspin-negative cell lines, Maspin expression was induced by treatment with 5-aza-2′-deoxycytidine, a DNA demethylating agent. Immunoreactivity for Maspin protein was frequently detected in UDTCs (8/13, 62%) and PDTCs (7/17, 41%). Immunoreactivity for Maspin was diffusely positive in UDTCs, and was restricted to dedifferentiated components of the tumor in PDTCs. Positive immunoreactivity was infrequent in WDTCs (1/56, 2%), and all follicular adenomas and normal thyroid glands were completely negative. Their methylation status evaluated by the methylation-specific PCR method showed a good inverse correlation with their immunoreactivity in surgically resected specimens. Our data suggest that overexpression of Maspin by DNA hypomethylation is closely associated with morphological dedifferentiation in thyroid cancers.

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Abbreviations

UDTCs:

undifferentiated thyroid cancers

RQ-PCR:

real-time quantitative PCR

5-aza-dC:

5-aza-2′-deoxycytidine

SNP:

single nucleotide polymorphism

WDTCs:

well differentiated thyroid cancers

PDTCs:

poorly differentiated thyroid cancers

MSP:

methylation-specific PCR

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Acknowledgements

We thank Drs Hideo Sugawa and Isamu Ishiwata for providing cell lines (HTC/C3 and HOTHC, respectively). We are also grateful to Ms Naoko Sasaki, Ms Sachiko Fujiwara and Mr Akihiko Ushirokawa for technical assistance.

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Authors and Affiliations

  1. Department of Pathology, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka, 020-8505, Japan

    Satoshi Ogasawara, Chihaya Maesawa, Kei Wada, Kentaro Fujisawa & Tomoyuki Masuda

  2. Department of Surgery 1, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka, 020-8505, Japan

    Satoshi Ogasawara, Masahide Yamamoto, Yuji Akiyama, Taro Higuchi, Yuki Tomisawa & Kazuyoshi Saito

  3. Department of Critical Care Medicine, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka, 020-8505, Japan

    Satoshi Ogasawara, Nobuhiro Sato & Shigeatsu Endo

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  1. Satoshi Ogasawara
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Correspondence to Satoshi Ogasawara.

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Supported by Grant-in-Aid for Scientific Research 14571222, 14571221 and 15790698 from the Japanese Ministry of Education, Science, Sports and Culture

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Ogasawara, S., Maesawa, C., Yamamoto, M. et al. Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers. Oncogene 23, 1117–1124 (2004). https://doi.org/10.1038/sj.onc.1207211

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