Expression of the microRNA-200 Family; a New Role for miRNAs in the Morphological Changes of Epstein-Barr Virus Associated Gastric Carcinoma
T Sakatani, A Shinozaki, T Ushiku, M Isogai, S Ishikawa, H Uozaki, M Fukayama. The University of Tokyo, Tokyo, Japan
Background: MicroRNAs (miRNAs) are small non-coding RNA molecules involved in the post-transcriptional regulation of gene expression, and their aberrant expression has been implicated in a wide variety of complex biological processes. Epstein-Barr virus (EBV)-associated gastric carcinoma especially stands out by its unique morphology, however, associations with specific miRNAs have yet to be elucidated.
Design: Thirty-one primary gastric carcinoma cases, as well as 31 samples corresponding normal tissues were investigated for the expression levels of miR-200a and miR-200b by the real time quantitative RT-PCR, and assessed the associations with EBV infection, E-cadherin expression, and other clinicopathological parameters. We established EBV-infected cell lines as models of EBV-asssociated gastric carcinoma and evaluated the effect of EBV infection in the aberrant expression of the miR-200 family and E-cadherin in vitro.
Results: There were 13 EBV-associated gastric carcinomas and 18 EBV-negative gastric carcinomas in this study. EBV-associated gastric carcinoma showed decreased expression levels of the miR-200 family compared with EBV-negative gastric carcinoma. The downregulation of the miR-200 family was observed in several gastric carcinoma cell lines infected recombinant EBV, compared with their original cell lines. Among them, one of the EBV-infected cell lines revealed a dramatic cell-to-cell adhesion, along with the reduction of E-cadherin expression and upregulation of its repressors ZEB1 and ZEB2. Transfection of these EBV-infected cells with precursors of the miR-200 family caused partial restortion of E-cadherin expression. Additionally, transfection of the original cell line with EBV-encoded small RNA (EBER)-gene resulted in the similar morphological changes.
Conclusions: Our results indicate that EBV infection to the epithelial cells causes down regulation of the miR-200 family, and leads to the reduction of the E-cadherin by upregulating its repressors ZEB1 and ZEB2. The loss of cell-to-cell adhesion is essential for the tumor to progress and EBERs play a role in this carcinogenic process. These findings provide some clues clarifying the viral oncogenesis in EBV-associated gastric carcinoma.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 64, Tuesday Afternoon