Downregulation of ZC3H13 by miR-362-3p/miR-425-5p is associated with a poor prognosis and adverse outcomes in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is notorious for its poor prognosis. Previous studies identified several N6methyladenosine (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.

METTL7B serves as a prognostic biomarker and promotes metastasis of lung adenocarcinoma cells

“…Among them, RNA methylation (m6A, N6-methyl-adenosine) modification as a post-transcriptional modification has become the most important anti-cancer research target ( 7 , 8 ). For example, miR-362-3p/miR-425-5p downregulation of ZC3H13 is linked to poor prognosis along with poor outcomes in hepatocellular carcinoma (HCC) ( 9 ). In gastric cancer, WTAP overexpression affects tumor-related T lymphocyte infiltration, which contributes to a poor prognosis ( 10 ).…”

RNA m6Amethylation in cancer

“…Less research has been done on the regulation of other m 6 A writers in cancers. For instance, Wu et al [163] reported that ZC3H13 could be down-regulated by miR-362-3p/miR-425-5p in hepatocellular carcinoma (HCC). Tran et al [5] showed that METTL5 formed a heterodimeric complex with TRMT112 to gain metabolic stability.…”

“…For instance, Wu et al. [ 163 ] reported that ZC3H13 could be down‐regulated by miR‐362‐3p/miR‐425‐5p in hepatocellular carcinoma (HCC). Tran et al.…”

The role of RNA modification in hepatocellular carcinoma

“…ETS proto-oncogene 1 (ETS1) is a downstream effector of WTAP and WTAP-regulated m6A modification leads to posttranscriptional repression of ETS1, which promotes HCC progression through the human antigen R (HuR)-ETS1-p21/ p27 axis and is a potential target for HCC therapy (Chen et al, 2019c). Zinc finger CCCH domain-containing protein 13 (ZC3H13) is a potential HCC target for biomarker and therapy, is significantly downregulated in HCC, and downregulation of ZC3H13 mediated by miRNA 362-3p (miR-362-3p) and miRNA 5425-5p (miR-425-5p) is associated with poor prognosis and cancer immune invasion in HCC (Wu et al, 2022). As the largest known element of the m6A methyltransferase, KIAA1429 is shown to be highly upregulated in HCC tissues and related to poor prognosis in HCC patients (Cheng et al, 2019;Lan et al, 2019).…”