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

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 RASSFIA gene, located on a 120-kb minimal deletion region on 3p21.3, was frequently inactivated by promoter hypermethylation in NPC. We further confirmed that RASSFIA 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, FUSI, RASSFIC, BLU, NPRL2, 101F6, PL6 and CACNA2D2) in this 120-kb region were rare in NPC samples. The contribution of RASSFIA in NPC tumorigenesis was investigated by restoring its expression in a RASSFIA deficient cell line, C666-1. Transient transfection of wild-type RASSFIA resulted in marked growth inhibition in NPC cells. Isolated stable clones expressing wild-type RASSFIA 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 RASSFIA-transfected clones. Our results provide strong evidence to support RASSFIA as a target tumor suppressor gene on 3p21.3 in NPC. (C) 2004 Wiley-Liss, Inc.