Zhang Yu, Han Xu, Ren Jiayan, Zhu Man, Chu Dake, Zhang Yanmin, Su Qi, Zhang Zixi
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China.
Exp Dermatol. 2025 Mar;34(3):e70082. doi: 10.1111/exd.70082.
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.
基底细胞癌（BCC）是一种常见的皮肤癌，在全球范围内的发病率正在上升。以往的全基因组关联研究（GWAS）已经确定了某些与BCC相关的基因位点。然而，BCC的许多潜在致病基因仍有待发现。虽然音猬因子（SHH）信号通路以及PTCH1/2和SMO中的突变是BCC发病机制中已明确的驱动因素，但新的遗传因素可能会补充现有的治疗靶点，如维莫德吉和索尼德吉。孟德尔随机化（MR）研究使用了多个组学数据集，包括表达数量性状位点（eQTL）、甲基化数量性状位点（mQTL）和蛋白质数量性状位点（pQTL），以确定与发生BCC风险增加相关的遗传因素。然后对GEO数据库进行转录组分析，验证关键基因的特异性表达。此外，体外实验用于使关键基因沉默，以观察该基因对A431细胞增殖能力的影响。结合多组学MR分析结果，确定了6个与BCC风险相关的RCC2基因的CpG位点。此外，单细胞转录组分析证实了RCC2在BCC队列中的特异性表达。在体外验证实验中，将siRCC2-1/2转染到A431细胞中，显著降低了细胞中RCC2的表达。此外，敲低RCC2后，A431细胞的增殖受到显著抑制。我们通过基于MR的生物信息学分析确定了一个与BCC相关的风险基因RCC2，并证明抑制RCC2可在体外抑制A431的增殖。这些发现为BCC的靶向治疗提供了新策略。
