Identification of Androgen Receptor Variant 7-related RNAs Affecting Abiraterone Efficacy in Castration-resistant Prostate Cancer Treatment by RNA-sequencing

Abstract Background: This study aimed to identify androgen receptor variant 7 (AR-V7)-related RNAs affecting Abiraterone treatment of castration-resistant prostate cancer (CRPC) using RNA-sequencing. Methods: To identify AR-V7-related RNAs affecting Abiraterone treatment of CRPC, a series of in vitro experiments were employed, including cell proliferation assay, cell apoptosis assay, Western blot analysis, and Real-time quantitative reverse transcription PCR (qRT-PCR). After RNA-sequencing, the differentially expressed (DE) mRNAs and DE long non-coding RNAs (lncRNAs) were screened and the lncRNA-mRNA pairs were identified. In addition, enrichment and Protein-protein interaction (PPI) network analyses were performed. Finally, the mRNA-miRNA-lncRNA competing endogenous RNAs (ceRNA) network was built, along with survival analysis. Results: A total of 1,387 AR-V7-related RNAs affecting Abiraterone treatment of CRPC were identified. The enrichment analysis showed that the target genes of DEmRNAs and DElncRNAs were primarily involved in cancer-related pathways, including the ErbB signaling pathway, pathways in cancer, and basal cell carcinoma. In addition, notch receptor 1 (NOTCH1), ionotropic NMDA glutamate receptor type subunit 1 (GRIN1), U-box containing protein 1 (STUB1), and mitogen-activated protein kinase 7 (MAP2K7) with high degrees in the PPI network. Moreover, MAP2K7 was regulated by hsa-miR-6825-5p, which in turn was regulated by MAFG-AS1 lncRNA in the ceRNA network. The survival analysis revealed that a total of four lncRNAs, including MAFG-AS1, and 17 mRNAs, including high muscle blind-like splicing regulator 2 (MBNL2), were associated with disease-free survival (RFS). Among them, only MBNL2 overexpression correlated with good survival outcome. The NOTCH1, GRIN1, STUB1, MBNL2, and ErbB signaling pathways are likely related to the efficacy of Abiraterone in CRPC treatment. Moreover, the MAFG-AS1-hsa-miR-6825-5p-MAP2K7 axis could be a therapeutic target for Abiraterone in CRPC treatment.Conclusions: NOTCH1, GRIN1, STUB1, MBNL2, and the ErbB signaling pathway may relate to the progression of CRPC. MAFG-AS1-hsa-miR-6825-5p-MAP2K7 axis might be a potential therapeutic target for Abiraterone in CRPC.