Xia Xigang, Zhang Hao, Xia Peng, Zhu Yimin, Liu Jie, Xu Kequan, Yuan Yufeng
Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China.
Front Oncol. 2021 Aug 30;11:733595. doi: 10.3389/fonc.2021.733595. eCollection 2021.
High glycolysis efficiency in tumor cells can promote tumor growth. lncRNAs play an important role in the proliferation, metabolism and migration of cancer cells, but their regulation of tumor glycolysis is currently not well researched.
We analyzed the co-expression of glycolysis-related genes and lncRNAs in The Cancer Genome Atlas (TCGA) database to screen glycolysis-related lncRNAs. Further prognostic analysis and differential expression analysis were performed. We further analyzed the relationship between lncRNAs and tumor immune infiltration. Since WAC antisense RNA 1 (WAC-AS1) had the greatest effect on the prognosis among all screened lncRNAs and had a larger coefficient in the prognostic model, we chose WAC-AS1 for further verification experiments and investigated the function and mechanism of action of WAC-AS1 in hepatocellular carcinoma.
We screened 502 lncRNAs that have co-expression relationships with glycolytic genes based on co-expression analysis. Among them, 112 lncRNAs were abnormally expressed in liver cancer, and 40 lncRNAs were related to the prognosis of patients. Eight lncRNAs (WAC-AS1, SNHG3, SNHG12, MSC-AS1, MIR210HG, PTOV1-AS1, AC145207.5 and AL031985.3) were used to established a prognostic model. Independent prognostic analysis (P<0.001), survival analysis (P<0.001), receiver operating characteristic (ROC) curve analysis (AUC=0.779) and clinical correlation analysis (P<0.001) all indicated that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor (P<0.001). The risk score and lncRNAs in the model were found to be related to a variety of immune cell infiltration and immune functions. WAC-AS1 was found to affect glycolysis and promote tumor proliferation (P<0.01). WAC-AS1 affected the expression of several glycolysis-related genes (cAMP regulated phosphoprotein 19 (ARPP19), CHST12, MED24 and KIF2A) (P<0.01). Under hypoxic conditions, WAC-AS1 regulated ARPP19 by sponging miR-320d to promote glucose uptake and lactate production (P<0.01).
We constructed a model based on glycolysis-related lncRNAs to evaluate the prognostic risk of patients. The risk score and lncRNAs in the model were related to immune cell infiltration. WAC-AS1 can regulate ARPP19 to promote glycolysis and proliferation by sponging miR-320d.
肿瘤细胞中高糖酵解效率可促进肿瘤生长。长链非编码RNA（lncRNAs）在癌细胞的增殖、代谢和迁移中起重要作用，但其对肿瘤糖酵解的调控目前研究较少。
我们分析了癌症基因组图谱（TCGA）数据库中糖酵解相关基因与lncRNAs的共表达，以筛选糖酵解相关lncRNAs。进一步进行预后分析和差异表达分析。我们进一步分析了lncRNAs与肿瘤免疫浸润之间的关系。由于WAC反义RNA 1（WAC-AS1）在所有筛选出的lncRNAs中对预后影响最大，且在预后模型中系数较大，我们选择WAC-AS1进行进一步验证实验，并研究WAC-AS1在肝细胞癌中的功能及作用机制。
基于共表达分析，我们筛选出502个与糖酵解基因有共表达关系的lncRNAs。其中，112个lncRNAs在肝癌中异常表达，40个lncRNAs与患者预后相关。使用8个lncRNAs（WAC-AS1、SNHG3、SNHG12、MSC-AS1、MIR210HG、PTOV1-AS1、AC145207.5和AL031985.3）建立了一个预后模型。独立预后分析（P<0.001）、生存分析（P<0.001）、受试者工作特征（ROC）曲线分析（AUC=0.779）和临床相关性分析（P<0.001）均表明该预后模型具有良好的预测能力，风险评分可作为独立预后因素（P<0.001）。发现模型中的风险评分和lncRNAs与多种免疫细胞浸润及免疫功能相关。发现WAC-AS1影响糖酵解并促进肿瘤增殖（P<0.01）。WAC-AS1影响多个糖酵解相关基因（环磷酸腺苷调节磷蛋白19（ARPP19）、CHST12、MED24和KIF2A）的表达（P<0.01）。在缺氧条件下，WAC-AS1通过海绵吸附miR-320d调节ARPP19，促进葡萄糖摄取和乳酸生成（P<0.01）。
我们构建了一个基于糖酵解相关lncRNAs的模型来评估患者的预后风险。模型中的风险评分和lncRNAs与免疫细胞浸润相关。WAC-AS1可通过海绵吸附miR-320d调节ARPP19，促进糖酵解和增殖。
