GACAT3-FASN ceRNA调控网络影响胃癌细胞脂肪酸代谢的分子机制

Since uncertainty remains about the exact molecular mechanism of lipid metabolism disorder in gastric cancer (GC), it is of great significance to explore the role of newly discovered regulatory molecules in the pathological process. As shown in earlier studies by the author group, long non-coding RNA-GACAT3, a newly discovered GC-associated molecule, is over-expressed in GC tissues, GC cell lines and plasma in patients with gastric cancer, which could be significantly associated with GC metastasis. Aiming at discovery of the physiological and pathological roles of GACAT3 in the development of gastric cancer, we take into consideration of some latest data of gene chip hybridization, which showed that microRNA-497 be low-expressed in GC, and we propose via bioinformatics predicting and experimental validation that both GACAT3 and the key enzyme of de novo synthesis of long-chain fatty acids-fatty acid synthase (FASN) are target genes of miR-497. Our hypothesis, therefore, is that GACAT3 serves as a competing endogenous RNA to regulate the fatty acid metabolism and proliferation of GC cells mediated by FASN. In this sense, this project is intended to elucidate the role of GACAT3 in the regulation of fatty acid metabolism in GC cell lines by constructing GC associated ceRNA network, enrichment of pathways in KEGG, data mining of clinical data in TCGA database, RIP system, RNA pull-down system and also the model of nude mice bearing gastric cancer. In a longer perspective, findings and problems in this project are expected to provide new clues for uncovering mechanism of gastric carcinogenesis.

胃癌脂代谢紊乱的具体分子机制还远未被明确，阐述某些新调控分子在该过程中所扮演的角色，对揭示胃癌发生的分子机制有具较为重要的意义。我们前期研究表明，长链非编码RNA—GACAT3在胃癌组织、细胞及血浆中高表达，其水平与胃癌的转移密切相关，是一个新发现的癌相关分子。但其在胃癌发生中的作用机制仍缺乏全面了解。我们最近运用芯片技术筛选到微小RNA-497在胃癌组织中低表达，预测和验证实验发现它同时负调控GACAT3和脂肪酸合成的关键酶—脂肪酸合酶(FASN)。我们推测，GACAT3可能以竞争性内源RNA机制介导FASN表达来调控胃癌细胞脂肪酸代谢。为此，本课题拟进一步运用胃癌相关ceRNA网络构建、KEGG通路富集、TCGA数据库数据挖掘、RIP技术、RNA pull-down技术及荷瘤裸鼠模型等方法，阐明GACAT3调控胃癌细胞脂肪酸代谢的可能机制，结果将为揭示胃癌的发生机制提供新线索。

代谢异常是恶性肿瘤的一个显著特征，揭示某些新发现的调控分子在该过程中的作用机制，对明确胃癌发生发展具有重要的意义。我们前期研究表明，长链非编码RNA—GACAT3在胃癌中高表达，表达水平与胃癌的转移密切相关，但其在胃癌发生中的作用机制仍不清楚。我们运用芯片技术筛选到微小RNA-497在胃癌组织中低表达，预测和验证实验发现它可负调控GACAT3和脂肪酸合酶(FASN)。通过运用构建胃癌ceRNA网络、KEGG通路分析、TCGA数据库筛选等方法，结果表明，GACAT3可以竞争性内源RNA机制调控FASN表达，进一步调控胃癌脂肪酸代谢，这些机制的明确，为胃癌的早期诊断及治疗提供了新的候选靶点。