Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer

Abstract

Abstract. RAPGEF1 (also known as C3G and GRF2) is a guanine nucleotide exchange factor that releases GDP from the inactive Rap1 protein, facilitating its subsequent activation by the binding of GTP. Rap1 plays regulatory roles in proliferation, differentiation and apoptosis. Amplification and overexpression of RAPGEF1 have been found in small cell lung cancers, suggesting an oncogenic role. In contrast, hypermethylation of a promoter CpG island (CGI-A) of RAPGEF1 has been reported in squamous cervical tumors, suggesting an anti-oncogenic role in these gynecological cancers. In our studies of DNA methylation alterations in gastrointestinal cancer we found somatic demethylation of a relaxed-criterion CpG island (CGI-B) located in the first intron of RAPGEF1 in 40% of colon cancers and 8% of gastric cancers relative to their matching normal tissues that were always methylated. We also found somatic demethylation in 47% of squamous cervical carcinomas as well as 33% of ovarian cancers. This somatic change in methylation, however, did not extend to the strict-criterion CpG island located in the promoter region (CGI-A) that was unmethylated in all normal and tumor tissues analyzed. Thus, promoter hypermethylation of RAPGEF1 seems insignificant in colorectal, cervical and ovarian cancers.In contrast, tumor-specific hypomethylation of the gene appears to be frequent in gastrointestinal and gynecological cancers. IntroductionOur previous analysis of gastrointestinal cancer by methylationsensitive amplification fragment length polymorphism (MS-AFLP) (1,2) identified several genomic sequences that exhibited methylation alterations in colorectal and gastric cancers (1). One of them (named band CA-8) appeared hypomethylated in colorectal and gastric cancers. Band CA-8 contains a NotI site located in the first intron of RAPGEF1 (GeneID: 2889, chr 9q34.3). This gene functions as a guanine nucleotide exchange factor (GEF) of Rap1 that is involved in multiple effector pathways. Rap1 is known to inhibit MAPK activity by blocking the signal transduction from Ras to c-Raf-1 (3-5), activate the MAPK cascades via B-Raf (6), and activate other members of the MAPK family of proteins (7). Thus, RAPGEF1 can exert pleiotropic effects, promoting or inhibiting growth in different cellular contexts.The role of RAPGEF1 in cancer progression is unclear. On the one hand, it has been found that overexpression of exogenous RAPGEF1 blocks the anchorage-independent growth induced by cotransfected, activated, sis, ras and v-raf oncogenes in fibroblasts (8); on the other hand, amplification, upregulation and overexpression of endogenous RAPGEF1 have been reported in small cell lung carcinomas, suggesting that this gene can play an oncogenic role through derangement of the CRK-Rap1 signaling pathway (9). More recently, this gene has been reported to undergo silencing through promoter hypermethylation in squamous cervical cancers (10).We therefore extended the methylation analysis to a panel of squamous cervical tumors to compare the apparent disparity...

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