Chi Fanwu, Cao Yong, Chen Yuhan
Cardiovascular Surgery Department, The People's Hospital of Gaozhou, Gaozhou, China.
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Front Oncol. 2021 Feb 23;11:560506. doi: 10.3389/fonc.2021.560506. eCollection 2021.
The mA RNA methylation modulators play a crucial role in regulating hepatocellular carcinoma (HCC) progression. The circular RNA (circRNA) regulatory network in regulating mA RNA methylation modulators in HCC remains largely unknown. In this study, 5 prognostic mA RNA methylation modulators in HCC were identified from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. The differentially expressed microRNAs (DEmiRNAs) and circRNAs (DEcircRNAs) between paired tumor and normal tissues were screened out from TCGA and or Gene Expression Omnibus (GEO) database to construct the circRNA-miRNA- mA RNA methylation modulator regulatory network, which included three mA RNA methylation modulators (HNRNPC, YTHDF1, and YTHDF2), 11 DEmiRNAs, and eight DEcircRNAs. Among the network, hsa-miR-139-5p expression was negatively correlated with YTHDF1. Hsa-miR-139-5p low or YTHDF1 high expression was correlated with high pathological grade, advanced stage and poor survival of HCC. Additionally, cell cycle, base excision repair, and homologous recombination were enriched in YTHDF1 high expression group by GSEA. A hub circRNA regulatory network was constructed based on hsa-miR-139-5p/YTHDF1 axis. Furthermore, hsa_circ_0007456(circMAP2K4) was validated to promote HCC cell proliferation by binding with hsa-miR-139-5p to promote YTHDF1 expression. Taken together, we identified certain circRNA regulatory network related to mA RNA methylation modulators and provided clues for mechanism study and therapeutic targets for HCC.
N⁶-甲基腺嘌呤（m⁶A）RNA甲基化调节剂在调节肝细胞癌（HCC）进展中起关键作用。HCC中调节m⁶A RNA甲基化调节剂的环状RNA（circRNA）调控网络在很大程度上仍不清楚。在本研究中，从癌症基因组图谱（TCGA）和国际癌症基因组联盟（ICGC）项目中鉴定出HCC中的5种预后m⁶A RNA甲基化调节剂。从TCGA和/或基因表达综合数据库（GEO）中筛选出配对肿瘤组织与正常组织之间差异表达的微小RNA（DEmiRNAs）和环状RNA（DEcircRNAs），以构建circRNA-miRNA-m⁶A RNA甲基化调节剂调控网络，该网络包括3种m⁶A RNA甲基化调节剂（HNRNPC、YTHDF1和YTHDF2）、11种DEmiRNAs和8种DEcircRNAs。在该网络中，hsa-miR-139-5p表达与YTHDF1呈负相关。hsa-miR-139-5p低表达或YTHDF1高表达与HCC的高病理分级、晚期和不良生存相关。此外，基因集富集分析（GSEA）显示细胞周期、碱基切除修复和同源重组在YTHDF1高表达组中富集。基于hsa-miR-139-5p/YTHDF1轴构建了一个枢纽circRNA调控网络。此外，已证实hsa_circ_0007456（circMAP2K4）通过与hsa-miR-139-5p结合促进YTHDF1表达来促进HCC细胞增殖。综上所述，我们鉴定了与m⁶A RNA甲基化调节剂相关的特定circRNA调控网络，为HCC的机制研究和治疗靶点提供了线索。
