Identification of RCC2 as a Risk Gene Associated With Basal Cell Carcinoma and Experimental Validation

Abstract

Basal cell carcinoma (BCC) is a common type of skin cancer that is increasing in prevalence worldwide. Previous genome-wide association studies (GWAS) have identified certain genetic loci associated with BCC. However, many potential disease-causing genes of BCC remain to be discovered. While the sonic hedgehog (SHH) signalling pathway and mutations in PTCH1/2 and SMO are well-established drivers of BCC pathogenesis, novel genetic factors may complement existing therapeutic targets such as vismodegib and sonidegib. The Mendelian Randomization (MR) study used multiple omics datasets including expression quantitative trait loci (eQTL), methylation quantitative trait loci (mQTL), and protein quantitative trait loci (pQTL) to identify genetic factors associated with an increased risk of developing BCC. Transcriptome analysis of the GEO database then verified the specific expression of key genes. In addition, in vitro experiments were used to silence the key gene to observe the effect of this gene on the proliferation ability of A431 cells. Combined with the multi-omics MR Analysis results, six CpG sites were identified with the RCC2 gene associated with BCC risk. Additionally, single-cell transcriptome analysis confirmed the specific expression of RCC2 in the BCC cohort. In the in vitro validation experiment, siRCC2-1/2 was transfected into the A431 cells, significantly decreasing the expression of RCC2 in the cells. Moreover, the proliferation of A431 cells was significantly inhibited after RCC2 was knocked down. We identified a risk gene RCC2 associated with BCC by MR-based bioinformatics analysis and demonstrated that inhibition of RCC2 inhibited the proliferation of A431 in vitro. These findings provide new strategies for targeted therapy of BCC.