The Role Of TMEFF2 And Long Non-Coding RNA GAS1 In Gastric Carcinoma

SectionⅠ The role of TMEFF2 in gastric carcinomaThe m RNA expression microarray show TMEFF2 is decreased in gastric cancer tissues, however, its role and clinical implication in gastric cancer is poorly understood. Gene expression profile analyses were performed and Gene Set Enrichment Analysis(GSEA)was used to explore its gene signatures. AGS and MKN45 cells were transfected with TMEFF2 or control plasmids and analyzed for gene expression patterns, proliferation, and apoptosis. TMEFF2 expression was knocked down with small hairpin RNAs and the effects on genome stability were assessed. Interactions between TMEFF2 and SHP1 were determined by mass spectrometry and immunoprecipitation assays. Integrated analysis revealed TMEFF2 expression was significantly decreased in GC cases and its expression was negatively correlated with the poor pathologic stage, large tumor size and poor prognosis. Gene Set Enrichment Analysis(GSEA)in the TCGA and Jilin datasets revealed that cell proliferation, apoptosis and DNA damage-related genes were enriched in TMEFF2-lower expression patients. Gain of TMEFF2 function decreased cell proliferation by increasing of apoptosis and blocking of cell cycle in GC cells. The protein tyrosine phosphatase SHP-1 was identified as a binding partner of TMEEF2 and mediator of TMEFF2 function. TMEFF2 expression positively correlated with SHP-1 and a favorable prognosis was more likely in GC patients with higher levels of both TMEFF2 and SHP-1.Section Ⅱ The role of long non-coding RNA GAS1 in gastric carcinomaLong non-coding RNAs(lnc RNAs) play a role in carcinogenesis. However, the function of lnc RNAs in human gastric cancer remains largely unknown. In this study, we identified a novel lnc RNA, GAS1, by integrated analysis in gastric cancer tissues compared to normal gastric tissues. GAS1 expression was gradually increased from normal gastric tissue to precancerous lesion and to gastric cancer. High levels of GAS1 expression were associated with tumor size, metastasis and poor prognosis in gastric cancer. Furthermore, GAS1 affected gastric cancer cell proliferation, invasiveness and metastasis in mμltiple models. Mechanistically, GAS1 bound WDR5 histone methyltransferase and KAT2 A histone acetyltransferase, acted as a modular scaffold of WDR5 and KAT2 A complexes, coordinated their localization, and specified the histone modification pattern on target gene SOD2 and altered gastric cancer cell biology. Thus, GAS1 is mechanistically, functionally and clinically oncogenic in gastric cancer. Targeting GAS1 and its pathway may be meaningfμl for treating patients with gastric cancer.