Silencing of the maspin gene by promoter hypermethylation in thyroid cancer

Abstract

Maspin (mammary serpin) is a serine protease inhibitor member of the serpin family and a class II tumor suppressor, whose expression is lost in many advanced cancers. Maspin has been shown to inhibit cell motility, invasion, and metastasis; however, its precise role still remains to be verified. Altough the expression of maspin mRNA is low or absent in most human cancer cells, the maspin gene is rarely re-arranged or deleted. We hypothesized that aberrant promoter methylation of the maspin promoter participates in the silencing of maspin expression during neoplastic progression. In thyroid and thyroid neoplasms the effects of maspin are still unknown. To clarify the role of maspin in thyroid carcinogenesis, we searched for mRNA and protein expression, as well as for promoter methylation in 30 normal (tumor-free) thyroid tissues (NT), 35 follicular adenomas (FAD), 42 papillary carcinomas (PTC), 38 follicular carcinomas (FTC), 25 poorly differentiated carcinomas (PDTC), and 34 undifferentiated carcinomas (UTC). Maspin mRNA expression in combination with protein expression was not found in any of the NT cases, nor in FAD, FTC, PDTC, and UTC. In contrast, mRNA and protein expressions were noted in 71 and 69% of PTC, respectively. Maspin promoter methylation was found in 93% of NT, in 89% of FAD, in 92% of FTC and PDTC, and in 100% of UTC. In contrast to these high methylation rates, only 29% were methylated in PTC. In conclusion, we hypothesize that maspin mRNA expression in combination with protein expression represents a special feature in the cascade of PTC genesis. Our data suggest that promoter methylation-caused maspin repression plays a major role in gene balance and in the process of tumor determination and dedifferentiation in thyroids. We presume that methylation of the maspin gene promoter is a common, a likely, and an early event during the development of papillary thyroid carcinomas.