EPSTEIN-BARR-VIRUS LMP1 MODULATES THE MALIGNANT POTENTIAL OF GASTRIC-CARCINOMA CELLS INVOLVING APOPTOSIS

About 10% of gastric carcinomas including lymphoepithelioma-like carci noma and adenocarcinoma are associated with Epstein-Barr virus (EBV) i nfection, In EBV-associated gastric carcinomas, the tumor cells expres s Epstein-Barr nuclear antigen 1 (EBNA-1) but not EBNA-2, -3A, -3B, or -3C, leader protein, or latent membrane proteins (LMPs) because of ge ne methylation, Only a few exceptional cases have LMP1 expression in t umor cells as demonstrated by immunohistochemical studies, To elucidat e the biological effects of LMP1 and the significance of its restricte d expression in EBV-associated gastric carcinomas, the LMP1 gene was t ransferred into EBV-negative gastric carcinoma cell lines (SCM1 and TM C1) and into EBV-negative nasopharyngeal carcinoma (NPC) cells (HONE-1 ) as a control. The biological effects of LMP1 in gastric carcinoma ce lls were monitored in vitro and in vivo. These results showed that the consequence of LMP1 expression is a growth enhancement in NPC cells, but it is a growth suppression in gastric carcinoma cells, The LMP1-ex pressing gastric carcinoma cells had a reduced growth rate, colony-for ming efficiency, mean colony size, and tumorigenicity and a lower mali gnant cytological grade, The reduced growth rate, colony-forming effic iency, and mean colony size were partially reversible in vitro with tr eatment with LMP1 antisense oligonucleotide. In addition, enhanced apo ptosis was found in the LMP1-expressing gastric carcinoma cells. This suggests that LMP1 may negatively modulate the malignant potential of gastric carcinoma cells via an enhancement of apoptosis, We concluded that the restriction of LMP1 expression in EBV-associated gastric carc inomas may lead to a growth advantage for tumor cells by avoiding LMP1 apoptotic effects and immunologically mediated elimination.