Research Paper Volume 14, Issue 5 pp 2304—2319
Downregulation of ZC3H13 by miR-362-3p/miR-425-5p is associated with a poor prognosis and adverse outcomes in hepatocellular carcinoma
- 1 Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong, People’s Republic of China
- 2 Department of Medicine, Qingdao University, Qingdao 266071, Shandong, People’s Republic of China
- 3 Medical Animal Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong, People’s Republic of China
- 4 Department of Oncology, Weifang Yidu Central Hospital, Qingzhou 262509, Shandong, People’s Republic of China
Received: October 25, 2021 Accepted: February 22, 2022 Published: March 12, 2022https://doi.org/10.18632/aging.203939
How to Cite
Copyright: © 2022 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hepatocellular carcinoma (HCC) is notorious for its poor prognosis. Previous studies identified several N6-methyladenosine (m6A)-related genes that play key roles in the initiation and progression of HCC patients. In particular, the N6-methyladenosine RNA methylation regulator ZC3H13 could be a candidate as a novel biomarker and therapeutic target for hepatocellular carcinoma. In HCC, low expression of ZC3H13 was reported, but the molecular reason is unclear. In this study, we performed pan cancer analysis for ZC3H13 expression and prognosis using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data and found that ZC3H13 might be a potential tumor suppressor gene in HCC. Subsequently, miRNAs contributing to ZC3H13 downregulation were identified by a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. Finally, the miR-362-3p/miR-425-5p-ZC3H13 axis was identified as the most likely upstream miRNA-related pathway of ZC3H13 in HCC. Additionally, miR-362-3p/miR-425-5p mimic and inhibitor results were detected by quantitative real-time PCR (qPCR) analysis and western blotting. We identified an upstream regulatory mechanism of ZC3H13 in HCC, namely, the miR-362-3p/miR-425-5p-ZC3H13 axis. Moreover, the ZC3H13 level was significantly positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. Collectively, our findings elucidated that ncRNA-mediated downregulation of ZC3H13 was correlated with a poor prognosis and tumor immune infiltration in HCC. In conclusion, this study demonstrates that ZC3H13 is a direct target of miR-362-3p/miR-425-5p in liver hepatocellular carcinoma (LIHC) that regulates immune modulation in the microenvironment of LIHC.
m6A: N6-methyladenosine; LIHC: liver hepatocellular carcinoma; HCC: hepatocellular carcinoma; HBV: hepatitis B virus; HCV: hepatitis C virus; TCGA: The Cancer Genome Atlas; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; ZC3H13: zinc finger CCCH-type containing 13; OS: Overall survival; RFS: Recurrence free survival; qPCR: Quantitative Real-time PCR; GSEA: Gene set enrichment analysis; RBM15: RNA-binding motif protein 15; METTL14: methyltransferase like 14; WTAP: Wilms tumor 1 associated protein; FTO: fat mass- and obesity-associated protein; ALKBH5: alkb homolog 5.