Associations of individual and joint expressions of ERCC6 and ERCC8 with clinicopathological parameters and prognosis of gastric cancer

BACKGROUND: Excision repair cross-complementing group 6 and 8 (ERCC6 and ERCC8) have been implicated in ailments such as genetic diseases and cancers. However, the relationship between individual and joint expressions of ERCC6/ERCC8 and clinicopathological parameters as well as prognosis of gastric cancer (GC) still remains unclear. METHODS: In this study, protein expressions of ERCC6, ERCC8 and ERCC6-ERCC8 were detected by immunohistochemistry (IHC) in 109 paired GC and para-cancerous normal tissue samples. The mRNA expression was detected in 36 pairs of tissue samples. IHC results and RNA-seq data extracted from The Cancer Genome Atlas (TCGA) were used to explore the clinical value of ERCC6 and ERCC8 expression in GC. We further conducted protein-protein interaction analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and gene-gene interaction analysis to explore the function and regulation networks of ERCC6 and ERCC8 in GC. RESULTS: Individual and joint ERCC6/ERCC8 expression were significantly higher in adjacent normal mucosa compared with GC tissues. ERCC6 mRNA expression showed no difference in GC and paired tissues, while ERCC8 mRNA was significantly decreased in GC tissues. Protein expression of ERCC6, ERCC8, double negative ERCC6-ERCC8 and double positive ERCC6-ERCC8 and overexpressed ERCC6 mRNA were related to better clinicopathologic parameters, while overexpressed ERCC8 mRNA suggested worse parameters. Univariate survival analysis indicated that the OS was longer when ERCC6 protein expression and ERCC8 mRNA expression increased, and double negative ERCC6-ERCC8 expression was associated with a short OS. Bioinformatics analyses showed ERCC6 and ERCC8 were associated with nucleotide excision repair (NER) pathway, and six and ten gene sets were figured out to be related with ERCC6 and ERCC8, respectively. KEGG pathway showed that ERCC6/ERCC8 related gene sets were mainly involved in the regulation of PI3K/AKT/mTOR pathway. Direct physical interactions were found between ERCC6 and ERCC8. CONCLUSIONS: Individual and joint expressions of ERCC6/ERCC8 were associated with clinical features of GC. Protein expression of ERCC6, ERCC6-ERCC8, and mRNA expression of ERCC8 were related to prognosis of GC. ERCC6 and ERCC8 primarily function in the NER pathway, and may regulate GC progression through the regulation of PI3K/AKT/mTOR pathway.