Accumulated evidence indicates that CCAT1 functions as an oncogene in the progression of a variety of tumors. However, little is known as to how CCAT1 impacts tumorigenesis in human prostate cancer. In this study, we found from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center database that CCAT1 is highly upregulated in castration-resistant prostate cancer (CRPC) compared with androgen-dependent prostate cancer (ADPC). Higher level of CCAT1 leads to increased mortality in patients with CRPC. In vitro and in vivo studies show that CCAT1 promotes prostate cancer cell proliferation as well as the tumor growth of prostate cancer xenografts. Mechanistically, in cytoplasm, CCAT1 sponges MIR-28-5P to prevent the anticancer effect. In nucleus, CCAT1 acts as a scaffold for DDX5 (P68) and AR transcriptional complex to facilitate the expression of AR-regulated genes, thus stimulating CRPC progression. Our findings suggest that CCAT1 is an oncogenic factor in the progression of CRPC with different regulatory mechanisms in the nucleus and cytoplasm of cells.

Though androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration-resistant prostate cancer (CRPC) which is the main cause of PCa death. Therefore, the identification of novel molecular mechanism regulating cancer progression and achievement of new insight into target therapy would be necessary for improving the benefits of PCa patients. This study aims to study the function and regulatory mechanism of HOTAIR/EZH2/miR-193a feedback loop in PCa progression. MSKCC and TCGA datasets were used to identify miR-193a expression profile in PCa. Cell Counting Kit-8 (CCK-8) assays, colony formation, invasion, migration, flow cytometry, a xenograft model and Gene Set Enrichment Analysis were used to detect and analyze the biological function of miR-193a. Then, we assessed the role of HOTAIR and EZH2 in regulation of miR-193a expression by using plasmid, lentivirus and small interfering RNA (siRNA). Luciferase reporter assays and chromatin immunoprecipitation assays were performed to detect the transcriptional activation of miR-193a by EZH2 and HOTAIR. Further, qRT-PCR and luciferase reporter assays were conducted to examine the regulatory role of miR-193a controlling the HOTAIR expression in PCa. Finally, the correlation between HOTAIR, EZH2 and miR-193a expression were analyzed using In situ hybridization and immunohistochemistry. We found that miR-193a was significantly downregulated in metastatic PCa through mining MSKCC and TCGA datasets. In vitro studies revealed that miR-193a inhibited PCa cell growth, suppressed migration and invasion, and promoted apoptosis; in vivo results demonstrated that overexpression of miR-193a mediated by lentivirus dramatically reduced PCa xenograft tumor growth. Importantly, we found EZH2 coupled with HOTAIR to repress miR-193a expression through trimethylation of H3K27 at miR-193a promoter in PC3 and DU145 cells. Interestingly, further evidence illustrated that miR-193a directly targets HOTAIR showing as significantly reduced HOTAIR level in miR-193a overexpressed cells and tissues. The expression level of miR-193a was inversely associated with that of HOTAIR and EZH2 in PCa. This study firstly demonstrated that miR-193a acted as tumor suppressor in CRPC and the autoregulatory feedback loop of HOTAIR/EZH2/miR-193a served an important mechanism in PCa development. Targeting this aberrantly activated feedback loop may provide a potential therapeutic strategy.

Prostate cancer is still considered a significant health care challenge worldwide due in part to the distinct transformation of androgen‐dependent prostate cancer (ADPC) into treatment‐refractory castration‐resistant prostate cancer (CRPC). Consequently, there is an urgent need to explore novel molecular mechanisms underlying treatment resistance in ADPC. Although numerous studies have alluded to the role of miR‐200a in several cancers, the biological significance of miR‐200a in prostate cancer remains unknown. After performing microarray analysis and reanalysis of the publicly available Memorial Sloan Kettering Cancer Center dataset, miR‐200a expression was found higher in ADPC tissues and its expression was positively associated with survival of CRPC patients. In vitro studies showed that miR‐200a overexpression in CRPC cells markedly suppressed cellular proliferation and facilitated apoptosis. In vivo studies indicated that overexpression of miR‐200a inhibited growth and metastasis of prostate cancer. The luciferase reporter assay demonstrated that BRD4 is a direct target gene of miR‐200a and it could reverse miR‐200a‐mediated biological effects in prostate cancer cells. Most importantly, our findings indicated that miR‐200a suppresses the progression of CRPC by inhibiting the activation of BRD4‐mediated AR signaling. This finding provides the foundation for the development of more personalized therapeutic approaches for CRPC patients.

Growing evidence points at an association between microRNAs and tumor development. Although dysregulation of microRNA-103a-3p (miR-103a-3p) in multiple human cancers has been reported, its expression in prostate cancer (PCa) remains unknown and there is currently no research on the relationship between miR-103a-3p and tumor protein D52 (TPD52) in PCa. Our aim in this study was to explore the effect and potential mechanism of miR-103a-3p in PCa. qRT-PCR was performed to detected the level of miR-103a-3p in PCa tissues and cells, and in normal tissues. Colony, wound-healing, invasion, proliferation, and apoptosis assays were performed in search miR-103a-3p effect in PCa. TargetScan was used to predict potential targets of miR-103a-3p. Additionally, dual-luciferase reporter, western blot, and immunofluorescence assays were performed to detected the target gene of miR-103a-3p. Finally, we explore the differences in tumor xenograft experiments between nude mice injected with stably miR-103a-3p expressing cells and those expressing a miR-negative control. Low level of miR-103a-3p was detected in PCa tissues and cells, when compared with normal tissues. Enhancement of miR-103a-3p significantly inhibited migration and invasion of PCa cells, and negatively regulated expression of the oncogenic tumor protein D52 (TPD52) through direct binding to its 3’-UTR. Interestingly, overexpression of TPD52 significantly attenuated the effect of mir-103a-3p on PCa. Our study provides the first evidence that miR-103a-3p directly targets TPD52 and inhibits the proliferation and invasion of PCa. This finding helps clarify the role of mir-103a-3p-TPD52 axis in PCa and may provide new therapeutic targets for the disease.

Background: This study aimed to determine the potential utility of plasma fibrinogen as a prognostic factor in patients with bladder cancer (BCa) after radical cystectomy (RC). Methods: Patients with BCa who underwent RC from 2014 to 2019 were analyzed retrospectively. The indexes of plasma coagulation and fibrinolysis system factors were collected. Kaplan–Meier survival curves were used to calculate the overall survival (OS) and disease-free survival (DFS). The prognostic value of plasma fibrinogen was analyzed by using Cox regression model, and a nomogram of BCa based on plasma fibrinogen was generated by R software. Results: Among 145 patients, the optimal cut-off value of plasma fibrinogen was 3.14g/L. High level of plasma fibrinogen was related to the poor prognosis of patients with BCa, and plasma fibrinogen has a more accurate prognostic ability than other plasma coagulation and fibrinolysis system factors. Multivariate Cox regression analysis showed that plasma fibrinogen was an independent predictor of OS (> 3.14 vs ≤ 3.14 HR, 2.58, 95% CI = 1.28– 5.23; p = 0.008) and DFS (> 3.14 vs ≤ 3.14 HR, 2.60, 95% CI = 1.20– 5.65; p = 0.016), and the nomogram based on plasma fibrinogen had better accuracy and discrimination (area under the curve (AUC): OS = 0.741, DFS = 0.733). Conclusion: Plasma fibrinogen can be used as an independent predictor of OS and DFS for RC patients, and the nomogram based on plasma fibrinogen was a reliable model for predicting the prognosis after RC.