lncRNA-PGALT调控胰腺癌非经典谷氨酰胺代谢途径的作用及机制研究

Non-canonical pathway of glutamine metabolism is essential for tumor growth of pancreatic carcinoma (PC) and it may provide new targets for the treatment of PC. We also showed that blockage of the non-canonical pathway of glutamine metabolism significantly inhibits self-renewal and proliferation of PC cell and improve the efficacy of adjunct treatment. However, the regulatory mechanism of this pathway remains unclear. The long-noncoding RNA (lncRNA) plays an important role in tumor growth. Our previous study found that: ① lncRNA-PGALT is overexpressed in PC tissue and may enhance the non-canonical pathway of glutamine metabolism; ② RNA-protein interaction experiments suggested that lncRNA-PGALT may bind to hnRNPK; ③ Knockdown of lncRNA-PGALT or hnRNPK may both inhibit the glutamine metabolism in PC. In this way, we will perform experiments in vivo and vitro to elucidate the function and mechanism of lncRNA-PGALT in PC and how they modulate the non-canonical pathway of glutamine metabolism and tumor growth by binding hnRNPK. Furthermore, we will collect clinical data of PC patients to clarify the correlation of lncRNA-PGALT and clinicopathological features and prognosis in PC. Through this research implementation, it could provide new biomarkers and targets for individual therapy in patients with PC.

非经典谷氨酰胺代谢途径是胰腺癌赖以生存的代谢途径，有望成为胰腺癌治疗的新靶点。我们亦证实阻断此代谢途径可有效抑制胰腺癌细胞的自我更新和增殖能力，并提高辅助治疗的疗效，但此途径的上游调控机制远未阐明。长链非编码RNA（lncRNA）在肿瘤细胞中起关键的调控作用，我们的前期结果发现：①基因芯片筛选发现lncRNA-PGALT在胰腺癌中过表达，并可能促进非经典谷氨酰胺代谢途径活性；②RNA-蛋白相互作用实验发现lncRNA-PGALT与hnRNPK结合；③下调lncRNA-PGALT或hnRNPK均可抑制胰腺癌的谷氨酰胺代谢水平。在此基础上，本课题拟继续开展：①阐明lncRNA-PGALT通过hnRNPK调控非经典谷氨酰胺代谢，促进胰腺癌细胞增殖的分子机制；②明确lncRNA-PGALT在胰腺癌临床病理学特征、预后中的意义。拟通过本项目的研究，为胰腺癌靶向治疗提供新思路。

非经典谷氨酰胺代谢途径是胰腺癌赖以生存的代谢途径，有望成为胰腺癌治疗的新靶点，前期证实阻断此代谢途径可有效抑制胰腺癌细胞的自我更新和增殖能力，并提高辅助治疗的疗效，但目前此途径的上游调控机制远未阐明。长链非编码RNA（lncRNA）在肿瘤细胞中起关键的调控作用，该项目在前期研究的基础上进一步探索，通过体内外实验进一步证实了lncRNA-PGALT对胰腺癌非经典谷氨酰胺代谢途径及生物学功能的影响；通过RNA-蛋白相互作用的研究方法，明确lncRNA-PGALT与hnRNPK结合，并发现FGFR和EGFR是lncRNA-PGALT/hnRNPK途径的下游靶点；通过临床病例分析分析了lncRNA-PGALT表达与胰腺癌临床病理学特征及预后的关系。该项目共发表研究成果论文2篇。