Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Abstract

The methylthioadenosine phosphorylase (MTAP) gene is located on 9p21 telomeric to the CDKN2A tumor suppressor gene. Loss of MTAP gene is frequently associated with CDKN2A homozygous deletion. Although the homozygous deletion of MTAP has been reported in various human cancers, its function in gastric carcinogenesis is unknown. Here, we determined the status of the MTAP gene by using a combination of array-based comparative genomic hybridization and oligonucleotide microarray. It was found that MTAP was deleted and downregulated in 2 of 10 gastric cancer cell lines. Of the 494 primary gastric carcinomas examined, MTAP expression at the protein level was reduced in 59 (11.9%). Furthermore, a lack of MTAP expression was found to be associated with poor survival (P = 0.038). The genomic loss of MTAP and CDKN2A in gastric carcinomas was investigated by quantitative real-time PCR. Among 20 gastric carcinomas, two cases showed deletion of both MTAP and CDKN2A, and three samples showed homozygous deletion of MTAP, but not of CDKN2A. An analysis of gastric carcinomas revealed that reduced MTAP expression correlated significantly with a genomic deletion. Furthermore, functional assays by transfecting the siRNA or the expressional cDNA into gastric cancer cell lines demonstrated that MTAP regulates cell growth and invasion. The present study suggests that MTAP plays an important role in the regulation of gastric carcinogenesis and, in particular, that MTAP loss is implicated in some way with tumor growth via the modulation of cellular properties, which, in turn, suggests that MTAP has therapeutic applications.

Homozygous deletions at 3p22, 5p14, 6q15, and 9p21 result in aberrant expression of tumor suppressor genes in gastric cancer

“…For instance, CDKN2A, PTEN, RB1, and SMARCB1 are often homozy-gously deleted in cancer (Cox et al, 2005). ADAM23 and MTAP, genes that function as tumor suppressors, are often homozygously deleted in GC (Takada et al, 2005a;Kim et al, 2011). However, many homozygously deleted genes in GC remain to be evaluated.…”

Expression ofMTAPInhibits Tumor-Related Phenotypes in HT1080 Cells via a Mechanism Unrelated to Its Enzymatic Function

“…Re-expression of MTAP in MTAP deleted MCF-7 breast cells results in loss of anchorage-independent growth in vitro and loss of tumor formation in vivo ( Christopher et al 2002 ). In addition, re-expression of MTAP in either a MTAP -deleted melanoma cell line or a gastric carcinoma cell line causes reduced cellular invasion in vitro ( Behrmann et al 2003 ; Kim et al 2011 ). Mice heterozygous for a germline deletion of MTAP die prematurely of T-cell lymphoma and have accelerated B-cell lymphoma onset when crossed to Eμ-myc mice ( Kadariya et al 2009 , 2013 ).…”

Loss of MTAP Expression is a Negative Prognostic Marker in Ewing Sarcoma Family of Tumors

“…MTAP is expressed in all normal tissues, but is often deleted in some tumors, mainly in co-deletion with the CDKN2A gene. Therefore, it is attributed a tumor suppression function to the MTAP gene [4,16]. In normal cells, the MTAP protein acts on the purine biosynthesis pathway, being important to the salvage process of adenine and methionine by cleaving the substrate 5 -deoxy-5 -Methylthioadenosine (MTA) generated during the biosynthesis of polyamines, and producing adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which is later converted to methionine.…”