Construction of Bone Metastasis-Specific Regulation Network Based on Prognostic Stemness-Related Signatures in Prostate Cancer

Abstract

Background: We planned to uncover the cancer stemness-related genes (SRGs) in prostate cancer (PCa) and its underlying mechanism in PCa metastasis.

Methods: We acquired the RNA-seq data of 406 patients with PCa from the TCGA database. Based on the mRNA stemness index (mRNAsi) calculated by one-class logistic regression (OCLR) algorithm, SRGs in PCa were extracted by WGCNA. Univariate and multivariate regression analyses were applied to uncover OS-associated SRGs. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Pearson's correlation analysis were performed to discover the possible mechanism of PCa metastasis. The significantly correlated transcription factors of OS-associated SRGs were also identified by Pearson's correlation analysis. ChIP-seq was applied to validate the binding relationship of TFs and OS-associated SRGs and spatial transcriptome and single-cell sequencing were performed to uncover the location of key biomarkers expression. Lastly, we explored the specific inhibitors for SRGs using CMap algorithm.

Results: We identified 538 differentially expressed genes (DEGs) between non-metastatic and metastatic PCa. Furthermore, OS-associated SRGs were identified. The Pearson correlation analysis revealed that FOXM1 was significantly correlated with NEIL3 (correlation efficient =0.89, p < 0.001) and identified hallmark_E2F_targets as the potential pathway mechanism of NEIL3 promoting PCa metastasis (correlation efficient =0.58, p < 0.001). Single-cell sequencing results indicated that FOXM1 regulating NEIL3 may get involved in the antiandrogen resistance of PCa. Rottlerin was discovered to be a potential target drug for PCa.

Conclusion: We constructed a regulatory network based on SRGs associated with PCa metastasis and explored possible mechanism.