ERCC3 serves as a prognostic biomarker for hepatocellular carcinoma and positively regulates cell proliferation and migration

Abstract

Background ERCC3 is an important member of the nucleotide excision repair (NER) pathway, and its overexpression is involved in the development of a variety of cancers and is a potential factor for poor tumor prognosis. Currently, the expression and function of ERCC3 in hepatocellular carcinoma (HCC) remain unclear. Methods The aim of this study was to investigate the expression and clinical significance of ERCC3 in HCC tissues. The differential expression of ERCC3 across cancers and the characteristics of genetic variation were evaluated using the TCGA database. The TCGA, GEO and ICGC datasets were combined to examine the expression and prognostic value of ERCC3 in HCC. The independent prognostic value of ERCC3 expression levels in HCC was explored based on Cox regression analysis, Kaplan‒Meier survival analysis, receiver operating characteristic (ROC) curves and nomograms. The ssGSEA method was used to determine the pathway association coefficients to reveal the biological function of ERCC3 in HCC and the potential clinical efficacy of immunotherapy. An ERCC3-overexpressing lentivirus was used to infect HepG2 cells and establish a stable transient cell line, and RTCA, wound healing, and Transwell assays were applied to detect the effects of ERCC3 on the biological phenotypes of HCC cells. Flow cytometry was used to detect the distribution of the cell cycle and apoptosis. Transcriptome sequencing was used to explore the effect of ERCC3 gene overexpression on the expression of genes involved in signaling pathways in HCC. Results The results showed that ERCC3 appeared to be abnormally expressed in a variety of tumors, that ERCC3 mRNA and protein expression levels were significantly greater in HCC tissues than in normal tissues, and that high ERCC3 expression was significantly correlated with poor survival in HCC patients. Multivariate Cox regression analysis revealed that the ERCC3 expression level was an independent prognostic factor for overall survival (P = 0.014). The gene set associated with the high ERCC3 group was significantly involved in multiple immune pathways and tumor progression-related pathways, and ERCC3 expression was significantly associated with immune checkpoints in HCC. The overexpression of the ERCC3 gene promoted HCC cell proliferation and migration and affected cell cycle progression. Transcriptome sequencing analysis revealed that the overexpression of ERCC3 regulated HCC cell proliferation, participated in multiple proinflammatory pathways, induced the formation of an inflammatory microenvironment in tumors, and promoted HCC progression. Conclusions High expression of ERCC3 may be a poor prognostic factor for HCC patients and may play an immunomodulatory role in HCC, providing a theoretical basis for the development of targeted immunotherapy for hepatocellular carcinoma.