Cathepsins and Skin Cancer (Malignant Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma): Insight From Genetic Correlation and Mendelian Randomization

Xianglong Li,1 Shaofeng Yang,2 Zhong Du,1 Wanying Xie,1 Man Zhu,1 Ling Han,1 Qingyu Zhou1 1Department of Medical and Radiation Oncology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Qingyu Zhou, Email [email protected]: Multiple studies have indicated that cathepsins (Cats) play a crucial role in the development and progression of skin cancer. However, most of these studies are observational and may be influenced by external variables, necessitating further research to establish causal relationships.Methods: We conducted a two-sample, two-way Mendelian randomization (MR) study utilizing pooled data from genome-wide association studies (GWAS) to evaluate the causal association between 9 Cats (Cat-B, E, F, G, H, L2, O, S, and Z) and 3 types of skin cancer, including malignant melanoma (MM), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Our analysis employed several methods, including inverse variance weighting (IVW), MR-Egger, weighted median, Cochran’s Q test, the MR-Egger intercept test, and leave-one-out sensitivity analysis. Furthermore, bioinformatics analysis of loci linked to Cats and skin cancer was performed to explore potential molecular mechanisms.Results: Genetically predicted increases in Cat-F and Cat-O levels were found to be correlated with a higher risk of BCC, while increased levels of Cat-L2 and Cat-O were associated with a reduced incidence of SCC. Bioinformatics analysis suggested that differentially expressed genes located near Cats-related loci could potentially influence BCC and SCC by modulating relevant signaling pathways and the tumor microenvironment.Conclusion: Our research indicated a causal link between Cats and skin cancer. By conducting a bioinformatic analysis of genetic loci related to Cats and skin cancer, we were able to gain a better understanding of the potential molecular mechanisms driving this association. This research can provide valuable insights into the diagnosis and treatment of skin cancer.Keywords: Cathepsins, Skin cancer, Genome-wide association study, Mendelian randomization, Bioinformatic analysis