Molecular mechanisms, immune cell infiltration, and potential drugs for prostate cancer

Article type: Research Article

Authors: Yan, Yunkun^{a; b; c; f} | Mao, Xingning^{c; d; e} | Zhang, Qingyun^{a; b; c} | Ye, Yu^{a; b; c} | Dai, Yan^{c; d; e} | Bao, Mengying^{c; d; e} | Zeng, Yanyu^{c; d; e} | Huang, Rong^{c; d; e} | Mo, Zengnan^{a; b; c; d; e; *}

Affiliations: [a] Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi, China | [b] Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi, China | [c] Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China | [d] Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Guangxi, China | [e] Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, Guangxi, China | [f] Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China

Correspondence: [*] Corresponding author: Zengnan Mo, Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Guangxi 530021, China. Tel.: +86 771 5353342; Fax: +86 771 5353342; E-mail: [email protected].

Abstract: BACKGROUND: The molecular mechanisms involved in the prostate cancer and their relationship with immune cell infiltration are not fully understood. The prostate cancer patients undergoing standard androgen deprivation therapy eventually develop castration resistant prostate cancer (CRPC) for which there is no effective treatment currently available, and the hub genes involved in this process remain unclear. OBJECTIVE:To study prostate cancer systematically and comprehensively. METHODS:Differentially expressed genes (DEGs) of prostate cancer were screened in The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Connectivity Map (Cmap) software was applied to discover potential treatment drugs. A protein-protein interaction (PPI) analysis was performed to obtained the hub genes, and the relationship between hub genes and immune cell infiltration was investigated. Next, RNAseq data of hormone-sensitive prostate cancer samples and CRPC samples obtained from TCGA database was further analyzed to identify DEGs. Finally, a PPI analysis was performed to obtain the hub genes. RESULTS:A total of 319 DEGs were identified between prostate cancer samples and normal adjacent samples from TCGA database using comparative analysis. The KEGG pathway analysis showed significant correlations with drug metabolism, metabolism of xenobiotics by cytochrome P450, and chemical carcinogenesis. AMACR, FOLH1 and NPY, three hub genes, were found to be upregulated. FOLH1 was positively correlated with CD8+ T cell infiltration. FOLH1, AMACR, and NPY were negatively correlated with CD4+ T cell infiltration. A total of 426 DEGs were identified from RNAseq data of hormone-sensitive prostate cancer samples and CRPC samples using further comparative analysis. KEGG pathway enrichment analysis showed significant correlations with arachidonic acid metabolism, PPAR signaling pathway, AMPK signaling pathway, and metabolic pathways. The top 10 hub genes in PPI network were screened out, including PPARG, SREBF1, SCD, HMGCR, FASN, PTGS2, HMGCS2, SREBF2, FDFT1, and INSIG1. Among them, SCD and FASN are expected to be the potential therapeutic targets for CRPC. CONCLUSIONS:AMACR, FOLH1 and NPY may be effective therapeutic targets and specific diagnostic markers for prostate cancer. AMACR, FOLH1, and NPY are also closely associated with immune cell infiltration in prostate cancer. Moreover, aminoglutethimide and resveratrol were found to be the promising drugs for treating prostate cancer. The progression of hormone-sensitive prostate cancer to CRPC may be related to arachidonic acid metabolism, PPAR signaling pathway, AMPK signaling pathway, and other metabolic pathways. SCD and FASN are expected to be the potential therapeutic targets for CRPC.

Keywords: TCGA, castration resistant prostate cancer, Cmap, immune cell infiltration

DOI: 10.3233/CBM-200939

Journal: Cancer Biomarkers, vol. 31, no. 1, pp. 87-96, 2021