Abstract
Background: ERCC3, a crucial component of the nucleotide excision repair pathway, is implicated in the development and progression of various cancers and is a potential indicator of poor prognosis. However, the expression and function of ERCC3 in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate the expression of ERCC3 in HCC tissues and its clinical significance, focusing on elucidating its potential mechanisms and therapeutic value in immunotherapy. Methods: The differential expression and genetic variation characteristics of ERCC3 across various cancers were evaluated using the TCGA database. The expression and prognostic value of ERCC3 in HCC were analyzed by integrating TCGA, GEO, and ICGC datasets. Independent prognostic value of ERCC3 expression levels in HCC was assessed using Cox regression analysis, Kaplan-Meier survival analysis, receiver operating characteristic curves, and nomograms. Pathway association scores were determined using ssGSEA to reveal the biological functions of ERCC3 in HCC and its potential clinical efficacy in immunotherapy. Stable transient cell lines were established by infecting HepG2 cells with lentivirus overexpressing ERCC3. The effects of ERCC3 on HCC cell biological phenotypes were evaluated using RTCA, wound healing, and Transwell assays. Cell cycle distribution and apoptosis were detected by flow cytometry. Transcriptome sequencing was performed to explore the impact of ERCC3 overexpression on the expression of signaling pathway-related genes in HCC. Results: The study revealed that ERCC3 is aberrantly expressed in various tumors, with significantly higher mRNA and protein levels in HCC tissues compared to normal tissues. High ERCC3 expression was significantly correlated with poor survival outcomes in HCC patients. Multivariate Cox regression analysis revealed that ERCC3 expression level is an independent prognostic factor for overall survival (P = 0.014). Gene sets associated with the high ERCC3 group were significantly involved in multiple immune pathways and tumor progression-related pathways, and ERCC3 expression was significantly correlated with immune checkpoints in HCC. Overexpression of ERCC3 promoted the proliferation and migration of HCC cells and influenced cell cycle progression. Transcriptome sequencing analysis indicated that ERCC3 overexpression regulated the proliferation of HCC cells, participated in multiple pro-inflammatory pathways, induced the formation of an inflammatory tumor microenvironment, and promoted HCC progression. Conclusion: This study is the first to reveal the association between high ERCC3 expression and poor prognosis in HCC and to elucidate its immunomodulatory role in HCC. Unlike previous studies, we found that ERCC3 promotes HCC progression by regulating the inflammatory microenvironment and immune checkpoints. These findings establish a novel theoretical foundation for the development of targeted immunotherapies for HCC and provide new insights into the molecular mechanisms underlying ERCC3's role in HCC.