LncRNA HOTTIP作为ceRNA调控胰腺癌干细胞谷氨酰胺代谢作用和机制研究

Cancer stem cells (CSCs) are the source of tolerance, metastasis and recurrence of pancreatic cancer. For the first time, we report that the unique non-classical glutamine (Gln) metabolism in pancreatic cancer is particularly important in the proliferation and maintenance of CSCs, and the down-regulation of GOT1 and GLS, which is the key enzyme, can significantly inhibit the CSCs. The function of long noncoding RNAs (lncRNAs) in Gln metabolism、CSCs and so on of pancreatic cancer were widely and deeply studied. It is first reported that lncRNA HOTTIP can be used as a marker for the diagnosis of pancreatic cancer, and to predict metastasis and chemotherapy resistance. It was further found that HOTTIP plays a key role in maintaining CSCs stemness. Preliminary studies showed that HOTTIP enhanced CSCs stemness by enhancing the expression of GOT1 and GLS. MiR-192 and miR-203 significantly inhibited the expression of HOTTIP, GOT1 and GLS by microRNAs high flux analysis and further experiments, suggesting that HOTTIP may promote the expression of GOT1 and GLS by adsorption of miR-192 and miR-203. According to the project put forward "HOTTIP ceRNA as the competitive binding of miR-192 and miR-203, promote pancreatic cancer CSCs by non-classical Gln metabolism" hypothesis. Through animal experiments, RNA pull -down and luciferase reporter gene technology and other methods to explore the molecular mechanism of HOTTIP, mediated miR-192 and miR-203 promote pancreatic cancer CSCs non-classical Gln metabolism key role and the mechanism, to provide a scientific basis to the new treatment targets for HOTTIP as a target for pancreatic cancer.

肿瘤干细胞（CSC）是胰腺癌治疗耐受、转移和复发的根源。我们首次报道胰腺癌独特的非经典谷氨酰胺（Gln）代谢在CSC干性方面尤其重要；下调其关键酶GOT1和GLS，明显损害CSC干性。前期对lncRNAs在胰腺癌Gln代谢和CSC等功能进行广泛深入研究。并首次报道HOTTIP可作为胰腺癌血液诊断标记物，预测转移、化疗耐药等重要功能。进一步发现HOTTIP在CSC干性起关键作用。预实验表明HOTTIP通过增强GOT1和GLS表达促进CSC干性。通过miRs高通量分析及预实验发现miR-192和-203明显抑制HOTTIP、关键酶的表达。据此本项目提出 “HOTTIP作为ceRNA促进胰腺癌CSC非经典Gln代谢”的假说。通过动物实验、免疫共沉淀和荧光素酶等技术探索分子机制，阐明HOTTIP介导miR-192和-203促进CSC非经典Gln代谢的关键作用及机制，为胰腺癌治疗新靶点提供科学依据。

肿瘤干细胞（CSC）是胰腺癌治疗耐受、转移和复发的根源。我们首次报道胰腺癌独特的非经典谷氨酰胺（Gln）代谢在CSC干性方面尤其重要；下调其关键酶GOT1和GLS，明显损害CSC干性。前期对lncRNAs在胰腺癌Gln代谢和CSC等功能进行广泛深入研究。并首次报道HOTTIP可作为胰腺癌血液诊断标记物，预测转移、化疗耐药等重要功能。进一步发现HOTTIP在CSC干性起关键作用。实验表明HOTTIP通过增强GOT1和GLS表达促进CSC干性。通过miRs高通量分析及动物实验、免疫共沉淀和荧光素酶实验发现miR-192和-203明显抑制HOTTIP、GOT1和GLS的表达。统分证据证明HOTTIP作为ceRNA促进胰腺癌CSC非经典Gln代谢。本项目阐明了HOTTIP介导miR-192和-203促进CSC非经典Gln代谢的关键作用及机制，有可能成为胰腺癌治疗新靶点提供科学依据。