Reduced expression and hypermethylation of HEADPIN, a serine proteinase inhibitor (serpin) in human squamous cell carcinoma

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Our in-house cDNA microarray system, which carries cDNAs derived from oligo-capped eDNA library of human oral cavity cancer cell lines, identified reduced expression of several genes in oral squamous cell carcinoma (OSCC). Thirteen genes were down-regulated 0.5-fold or more in common among four OSCC specimens of independent cases, compared with normal tissues. Among these genes, HEADPIN, which was isolated at chromosome 18q21.3, belongs to the member of serine proteinase inhibitor family (serpin). One of the functions of this gene family is believed to inhibit heamangiogenesis, invasion, and metastasis of tumors. RT-PCR revealed the down-regulation of HEADPIN gene expression in 17 (56.7%) of 30 primary OSCC samples and in 6 (66.7%) of 9 cell lines derived from OSCC. Furthermore, restoration of the HEADPIN gene mRNA was induced in five of six OSCC-derived cell lines showing down-regulation of the gene expression after treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. Thus, the down-regulation of HEADPIN expression contributes to the development of human OSCC and hypermethylation of the gene was confirmed to be one of the important mechanisms of inactivation of the HEADPIN gene in oral carcinogenesis.