Identification of Glycolysis-Related lncRNAs and the Novel lncRNA WAC-AS1 Promotes Glycolysis and Tumor Progression in Hepatocellular Carcinoma

Xigang Xia; Hao Zhang; Peng Xia; Yimin Zhu; Jie Liu; Kequan Xu; Yufeng Yuan

doi:10.3389/fonc.2021.733595

Identification of Glycolysis-Related lncRNAs and the Novel lncRNA WAC-AS1 Promotes Glycolysis and Tumor Progression in Hepatocellular Carcinoma

Front Oncol. 2021 Aug 30:11:733595. doi: 10.3389/fonc.2021.733595. eCollection 2021.

Authors

Xigang Xia^{1

2}, Hao Zhang^{1

2}, Peng Xia^{1

2}, Yimin Zhu^{1

2}, Jie Liu^{1

2}, Kequan Xu^{1

2}, Yufeng Yuan^{1

2}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
² Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China.

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: ARPP19; WAC-AS1; glycolysis; glycolysis-related lncRNAs; hepatocellular carcinoma; miR-320d; prognosis.