RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma

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Abstract
Deletion on the short arm of chromosome 3 is one of the most important genetic abnormalities in the tumorigenesis of nasopharyngeal carcinoma (NPC). Both physical mapping and functional studies have targeted an NPC-related tumor suppressor gene(s) to chromosome 3p21.3. We have reported recently that RASSF1A gene, located on a 120-kb minimal deletion region on 3p21.3, was frequently inactivated by promoter hypermethylation in NPC. We further confirmed that RASSF1A is the critical target tumor suppressor from 3p21.3, with the evidence that loss of expression and aberrant methylation of the other 8 candidate genes/transcripts (HYAL2, FUS1, RASSF1C, BLU, NPRL2, 101F6, PL6 and CACNA2D2) in this 120-kb region were rare in NPC samples. The contribution of RASSF1A in NPC tumorigenesis was investigated by restoring its expression in a RASSF1A deficient cell line, C666-1. Transient transfection of wild-type RASSF1A resulted in marked growth inhibition in NPC cells. Isolated stable clones expressing wild-type RASSF1A demonstrated retarded cell proliferation in vitro. Soft-agar assay also showed decreased number and sizes of colony formed in these clones. In vivo nude mice assay demonstrated the dramatic reduction of tumorigenic potential in the RASSF1A-transfected clones. Our results provide strong evidence to support RASSF1A as a target tumor suppressor gene on 3p21.3 in NPC.