ZC3H15 in human tumors: a pan-cancer exploration of its clinical significance, molecular function, and association with the tumor immune microenvironment

Abstract

Zinc finger CCCH-type protein 15 (ZC3H15) is a ribosome-associated eukaryotic protein involved in many biological processes, including gene expression regulation, translation, and immune modulation. Although ZC3H15 has been implicated in the development of certain tumors, its expression, functional relevance, diagnostic potential, and prognostic value in a pan-cancer context remain not fully elucidated. This study conducts an integrative, systematic, and comparative analysis of ZC3H15 across 33 cancer types and subsequently provides further experimental validation in liver cancer. mRNA expression data of ZC3H15 were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Protein level validations were performed using the Human Protein Atlas (HPA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The cBioPortal database was used to analyze the genomic alteration of ZC3H15. Two pathway enrichment analysis methods were conducted to explore the biological functions and molecular mechanisms of ZC3H15 in pan-cancer. The results indicated that ZC3H15 was overexpressed in a wide range of tumors. In certain cancers, particularly LIHC, LUAD, BRCA, LUSC, and HNSC, its expression was significantly correlated with poor patient prognosis. Mutations and amplifications were the most common gene alterations in ZC3H15. The GSCA database showed that methylation levels were reduced in most tumor types. Abnormal expression of ZC3H15 was related to immune cell infiltration. Gene enrichment analysis indicated that ZC3H15-related genes involved in tumor progression were significantly enriched in multiple cell cycle processes. We demonstrated that knockdown of ZC3H15 suppressed cell proliferation, migration, and invasion in two liver cancer cell lines, MHCC97H and Huh7, and two BRCA cell lines, MDA-MB-231 and Hs 578T. To further clarify the functional mechanism, subsequent immunofluorescence staining confirmed that ZC3H15 knockdown induced prometaphase arrest in MHCC97H and Huh7 liver cancer cells. Overall, this pan-cancer study demonstrates that ZC3H15 serves as a potential biomarker for cancer diagnosis, prognosis, and immune cell infiltration.