环状RNA0001756通过miRNA-185-3p/PGK1轴增加糖酵解促进胃癌增殖的机制研究

Glycolysis is the main way for energy in gastric cancer cells. Inhibition of glycolysis in gastric cancer cells suppresses tumor proliferation. However, the mechanism underlying is still unknown. In our previous studies, we employed both mRNAs and circRNAs microarrays to screen the differently expressed mRNAs and circRNAs that implicated in gastric cancer formation and progression. Self-Organizing Maps (SOM) analysis showed that circRNA0001756(circHIPK2) was upregulated in cancer tissues and positively correlated with the expression of a key glycolytic enzyme PGK1.Bioinformatics algorithms predicted that circHIPK2 could directly sponge miR-185-3p that targeting PGK1. Thus, we hypothesized that circHIPK2 regulated the expression of PGK1 by sponging miR-185-3p and promoted the glycolysis of gastric cancer cells which boosted their proliferation. To validate this hypothesis, we will do the clinical sample validation, nude mice Xenograft tumor model establishment and organoids formation, as well as other in vivo and in vitro measurements etc. To investigate the mechanisms underlying circHIPK2 mediated modulation of gastric cancer glycolysis metabolism and cancer proliferation. Our preliminary work might advance our understanding of circRNAs in metabolic modulation of gastric cancer and have therapeutic potential in gastric cancer treatment.

胃癌细胞的糖酵解途径是其主要的供能方式。糖酵解水平降低会导致胃癌细胞增殖能力下降，但其调控机制尚不清楚。我们前期通过胃癌组织mRNA和circRNA生物学芯片结合自组织映射神经网络(SOM)分析发现，显著高表达的circRNA0001756（circHIPK2）与糖酵解关键酶PGK1存在相互作用。生物信息学分析同时发现，circHIPK2可以靶向结合miRNA-185-3P,解除其对PGK1的作用。综合以上，本课题组提出科学假说：circHIPK2通过吸附miRNA-185-3p调控PGK1表达，提高糖酵解水平促进胃癌细胞的增殖。本项目将通过临床样本检测、裸鼠成瘤、细胞系及类器官功能实验等方法，从分子、细胞、组织和动物等层面探讨circHIPK2提高糖酵解水平促进胃癌增殖的机制。为寻找特异性针对胃癌糖酵解的治疗手段提供新思路。

打破肿瘤细胞高糖酵解的代谢特征是肿瘤治疗中亟待解决的问题。环状rna (CircRNAs)在糖酵解过程中发挥着重要作用。然而，hsa_circ_0001756在胃癌(GC)中的作用机制尚不清楚。hsa_circ_0001756在胃癌组织和细胞中的表达水平明显上调。在胃癌患者中，hsa_circ_0001756的表达水平与TNM分期和肿瘤大小密切相关。通过功能实验验证了hsa_circ_0001756的体外增殖和迁移能力。Hsa_circ_0001756不仅可以通过与多嘧啶束结合蛋白1( PTBP1)结合促进PGK1的表达和稳定性，还可以通过miR-185-3P/PGK1通路促进糖酵解。我们发现，以hsa_circ_0001756为中心的内源性RNA (ceRNA)类型和RBP调控关系可能会影响GC中的糖酵解过程。本研究为今后设计靶向肿瘤能量代谢通路的分子靶向药物提供了理论依据，为临床治疗胃癌提供了新的策略。