Journal of Hepatocellular Carcinoma (Nov 2022)
Integrated Analysis of Altered lncRNA, circRNA, microRNA, and mRNA Expression in Hepatocellular Carcinoma Carrying TERT Promoter Mutations
Abstract
Haibin Zhang,1 Xiaolu Zhang,1 Jingya Yu2 1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Department of Diagnostics, Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaCorrespondence: Jingya Yu, Department of Diagnostics, Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China, Tel +8653188382085, Email [email protected] and Objectives: Telomerase reverse transcriptase (TERT) promoter mutations are one of the most common mutations responsible for the development of hepatocellular carcinoma (HCC). Noncoding RNAs (ncRNAs) play a regulatory role in different cancers through the long noncoding RNA (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-mRNA axis. The aim of the study was to explore the influence of TERT promoter mutations on the ncRNA regulatory network in HCC.Methods: Four tumor samples with a wildtype TERT promoter and four tumor samples with TERT promoter mutations (sequencing cohort) were collected from HCC patients for high-throughput next-generation sequencing. Selected ncRNAs and mRNAs were validated by qPCR in 15 HCC tumors with a wildtype TERT promoter and seven HCC tumors with TERT promoter mutations (validation cohort, including the sequencing cohort).Results: In the mutant TERT promoter group, 536 lncRNAs, 21 circRNAs, 41 miRNAs, and 266 mRNAs were significantly up-regulated, while 1745 lncRNAs, 23 circRNAs, 32 miRNAs, and 1117 mRNAs were significantly down-regulated (P < 0.05) compared with the findings in wildtype group. AL360169.3-201, LINC02672-203, hsa_circ_0021412, hsa-miR-29b-1-5p, hsa-miR-4699-5p, hsa-miR-199a-5p, REG3A, SFRP5, and GSTM1 were verified at the RNA expression level to validate the sequencing results. A differentially expressed lncRNA/circRNA-miRNA-mRNA network was constructed to explore the effects of TERT promoter mutations on ncRNA regulation. Two ncRNA regulatory axes associated with TERT promoter mutations (hsa_circ_0003154/hsa_circ_0008952/IGLL5-AS1/LINC576/LINC575–hsa-miR-1260b –CLPTM1L/GSTM1 and hsa_circ_0031584/LINC2101–hsa-miR-214-3p–CD151) had carcinogenic potential.Conclusion: This study provides novel insights into the role of TERT promoter mutations on ncRNAs regulatory network in HCC progression.Keywords: hepatocellular carcinoma, TERT promoter mutations, lncRNA, circRNA, microRNA
