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Background: Radioresistance remains a significant obstacle in the treatment of prostate cancer (PCa). The mechanisms underlying the radioresistance in PCa remained to be further investigated. Methods: GSE53902 dataset was used in this study to identify radioresistance-related mRNAs. Protein-protein interaction (PPI) network was constructed based on STRING analysis. DAVID system was used to predict the potential roles of radioresistance-related mRNAs. Results: We screened and re-annotated the GSE53902 dataset to identify radioresistance-related mRNAs. A total of 445 up-regulated and 1036 down-regulated mRNAs were identified in radioresistance PCa cells. Three key PPI networks consisting of 81 proteins were further constructed in PCa. Bioinformatics analysis revealed that these genes were involved in regulating MAP kinase activity, response to hypoxia, regulation of the apoptotic process, mitotic nuclear division, and regulation of mRNA stability. Moreover, we observed that radioresistance-related mRNAs, such as PRC1, RAD54L, PIK3R3, ASB2, FBXO32, LPAR1, RNF14, and UBA7, were dysregulated and correlated to the survival time in PCa. Conclusion: We thought this study would be useful to understand the mechanisms underlying radioresistance of PCa and identify novel prognostic markers for PCa.

Jun Luo1 ,* Dan Wang2 ,* Xuechao Wan,2 Yangguang Xu,2 Yali Lu,2 Zhe Kong,2 Dujian Li,1 Wei Gu,1 Chenji Wang,2 Yao Li,2 Chaoneng Ji,2 Shaohua Gu,2 Yaoting Xu1 1Department of Urology, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaohua Gu; Yaoting Xu Email shaohuagu@fudan.edu.cn; ytxu64@vip.163.comIntroduction: Prostate cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of cancer-related death in males in the United States. Despite the initial efficacy of androgen deprivation therapy in prostate cancer (PCa) patients, most patients progress to castration-resistant prostate cancer. However, the mechanisms underlying the androgen-independent progression of PCa remain largely unknown.Methods: In this study, we established a PCa cell line (LNCaP-AI) by maintaining LNCaP cells under androgen-depleted conditions. To explore the cellular and molecular mechanisms of androgen-independent growth of PCa, we analyzed the gene expression patterns in androgen-independent prostate cancer (AIPC) compared with that in androgen-dependent prostate cancer (ADPC). KEGG pathway analysis revealed that Wnt signaling pathways were activated after androgen deprivation therapy (ADT). In vitro experiments showed that the inhibition of Wnt pathway reduced AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. Furthermore, WNT5A, LEF1 were identified as direct targets of AR by chromatin immunoprecipitation (ChIP) assay and public ChIP-seq datasets analysis.Results: In the present study, we found a regulatory mechanism through which crosstalk between androgen receptor (AR) and Wnt signals promoted androgen-independent conversion of PCa. The Wnt pathway was inhibited by androgen in androgen-dependent prostate cancer cells, but this blocking effect was not elicited in androgen-independent prostate cancer (AIPC) cells. Moreover, Wnt pathway genes WNT5A and LEF1 were directly downregulated by AR. In vitro experiments showed that inhibition of the Wnt pathways repressed AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. We found that WNT5A and LEF1 were downregulated in low-grade PCa but upregulated in metastatic PCa.Conclusion: In summary, we revealed that crosstalk between AR and Wnt signaling pathways promotes androgen-independent growth of PCa, which may provide novel therapeutic opportunities for castration-resistant prostate cancer.Keywords: Wnt pathway, prostate cancer, androgen receptor, androgen deprivation therapy