The short inverted repeats-induced circEXOC6B inhibits prostate cancer metastasis by enhancing the binding of RBMS1 and HuR.

Circular RNAs (circRNAs) are a novel class of endogenous RNAs with a covalently closed loop structure. Many circRNAs have been found to participate in cancer progression. However, the detailed generation process, functions, and related mechanisms of circRNAs in prostate cancer (PCa) remain largely unknown. In the present study, we identified circEXOC6B, a novel suppressor in the metastasis of PCa. Functionally, circEXOC6B, originating from the exocyst complex component 6B (EXOC6B) gene, inhibited migration and invasion of PCa in vitro and in vivo. Mechanistically, by acting as a protein scaffold, circEXOC6B enhanced the binding of human RNA binding motif single strand interacting protein 1 (RBMS1) and human antigen R (HuR) and further increased A-kinase anchoring protein 12 (AKAP12) expression to inhibit PCa metastasis. Unlike previous studies, we found that one pair of short inverted repeats in flanking introns at least partly promoted the circularization of circEXOC6B. Our study presents a novel mechanism for the inhibitory role of circEXOC6B in PCa metastasis and provides new insight into the molecular process of circRNA generation.

Circular RNA circSMARCA5 is a prognostic biomarker in patients with malignant tumor: a meta-analysis.

BACKGROUND: Malignant tumor is one of the most serious diseases endangering human health. Circular RNAs play an important role in the tumorigenesis and progression of various malignant tumors. Although various studies have investigated the biological function of circular RNA circSMARCA5 in malignant tumors, the prognostic value of circSMARCA5 in malignant tumor patients has not been systematically analyzed. METHODS: Relevant studies were obtained from the PubMed and Web of Science database. The quality of the enrolled studies was evaluated using the Newcastle-Ottawa Scale quality assessment system. Survival features and clinicopathological features were assessed using pooled hazard ratios and odds ratios with 95% confidence intervals, respectively. RESULTS: Overall, 7 relevant publications were enrolled in the meta-analysis. CircSMARCA5 expression was significantly correlated with better OS (HR = 0.51, 95%CI 0.41-0.65) or DFS/RFS/PFS (HR = 0.56, 95%CI 0.43-0.73) in malignant tumors. In the pooled analyses of clinicopathological characteristics, malignant tumors with higher circSMARCA5 were better differentiated (OR = 0.41, 95%CI 0.19-0.88). CircSMARCA5 expression was correlated with less advanced TNM stage (OR = 0.33, 95%CI 0.19-0.55). Moreover, malignant tumors with higher circSMARCA5 expression have less advanced lymph node metastasis (OR = 0.26, 95%CI 0.08-0.79). CONCLUSION: These results indicated that circSMARCA5 was a promising biomarker in malignant tumors, which may potentially facilitate clinical decisions in the future.

Anillin contributes to prostate cancer progression through the regulation of IGF2BP1 to promote c-Myc and MAPK signaling.

Prostate cancer (PCa), especially castration-resistant PCa, is a common and fatal disease. Anillin (ANLN) is an actin-binding protein that is involved in various malignancies, including PCa. However, the regulatory mechanism of ANLN in PCa remains unclear. Exploring the role of ANLN in PCa development and discovering novel therapeutic targets are crucial for PCa therapy. In the current work, we discovered that ANLN expression was considerably elevated in PCa tissues and cell lines when compared to nearby noncancerous prostate tissues and normal prostate epithelial cells. ANLN was associated with more advanced T stage, N stage, higher Gleason score, and prostate-specific antigen (PSA) level. In addition, we discovered that overexpression of ANLN promoted PCa cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, we performed RNA-seq to identify the regulatory influence of ANLN on the MAPK signal pathway. Furthermore, a favorable association between ANLN expression and IGF2BP1 expression was identified. The tumor-suppressive impact of ANLN downregulation on PCa cell growth was partially reversed by overexpressing IGF2BP1. Meanwhile, we discovered that ANLN can stabilize the proto-oncogene c-Myc and activate the MAPK signaling pathway through IGF2BP1. These findings indicate that ANLN could be a potential therapeutic target in PCa.

CircUBE3A(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis.

Metastatic progression is the primary cause of mortality in prostate cancer (PCa) patients. Although circular RNAs (circRNAs) have been implicated in cancer progression and metastasis, our current understanding of their role in PCa metastasis remains limited. In this study, we identified that circUBE3A(2,3,4,5), which originated from exons 2, 3, 4 and 5 of the human ubiquitin-protein ligase E3A (UBE3A) gene, was specifically downregulated in PCa tissues and correlated with the Gleason score, bone metastasis, and D'Amico risk classification. Through the in vitro and in vivo experiments, we demonstrated that overexpression of circUBE3A(2,3,4,5) inhibited PCa cell migration, invasion, metastasis, and proliferation. Mechanistically, circUBE3A(2,3,4,5) was found to bind to adenylate-uridylate-rich binding factor 1 (AUF1), promoting the translocation of AUF1 into the nucleus. This led to decreased AUF1 in the cytoplasm, resulting in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) mRNA instability and a subsequent reduction at the protein level. The downregulation of MTHFD2 further inhibited vimentin expression, thereby suppressing PCa cell epithelial-mesenchymal transition. Additionally, two pairs of the short-inverted repeats (TSIRs) in flanking introns were identified to synergistically facilitate the generation of circUBE3A(2,3,4,5) and other circRNAs. In summary, TSIRs-induced circUBE3A(2,3,4,5) acts as a suppressor of PCa metastasis by enhancing AUF1 nuclear translocation, reducing MTHFD2, and subsequently inhibiting vimentin expression. This study characterizes circUBE3A(2,3,4,5) as a functional circRNA and proposes it as a highly promising target for preventing PCa metastasis.

Cell-free DNA as a Promising Diagnostic Biomarker in Prostate Cancer: A Systematic Review and Meta-Analysis.

Objective: The detection of cell-free DNA (cfDNA) as a part of "liquid biopsy" of prostate cancer (PCa) has been widely explored. However, its diagnostic value for PCa remains controversial. Based on the data from the latest literature published in the past decade, the present review was conducted to clarify the diagnostic value of cfDNA in PCa. Methods: The related studies were systematically searched in the databases of PubMed, Embase, Web of Science, and Cochrane Library from January 1, 2010 to December 1, 2020. Sensitivity (SEN), specificity (SPE), and other relative parameters were pooled using a random model. Results: 14 eligible studies with 1049 PCa patients and 973 controls were selected based on the inclusion and exclusion criteria. Results demonstrated that cfDNA showed favorable SPE (0.89, 95% CI: 0.79, 0.94) but unsatisfied SEN (0.56, 95% CI: 0.43, 0.68) in the PCa diagnosis. The positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic odds ratios (DOR) were 5.1 (95% CI: 3.1, 8.5), 0.49 (95% CI: 0.39, 0.63), and 10 (95% CI: 6, 17), respectively. The summary receiver operating characteristic graph (SROC) with an area under the curve (AUC) of 0.80 (95% CI: 0.76, 0.83) was constructed which indicated favorable diagnostic accuracy for PCa. Results of the subgroup analysis and metaregression analysis reminded "ethnicity" and "methylation" might be sources of heterogeneity. The potential publication bias was not found using Deek's funnel plot asymmetry test (p > 0.05). Conclusions: Our meta-analysis illustrated that the cfDNA could undertake a promising role in the PCa diagnosis.

Deep Learning-Based Multi-Omics Integration Robustly Predicts Relapse in Prostate Cancer.

Objective: Post-operative biochemical relapse (BCR) continues to occur in a significant percentage of patients with localized prostate cancer (PCa). Current stratification methods are not adequate to identify high-risk patients. The present study exploits the ability of deep learning (DL) algorithms using the H2O package to combine multi-omics data to resolve this problem. Methods: Five-omics data from 417 PCa patients from The Cancer Genome Atlas (TCGA) were used to construct the DL-based, relapse-sensitive model. Among them, 265 (63.5%) individuals experienced BCR. Five additional independent validation sets were applied to assess its predictive robustness. Bioinformatics analyses of two relapse-associated subgroups were then performed for identification of differentially expressed genes (DEGs), enriched pathway analysis, copy number analysis and immune cell infiltration analysis. Results: The DL-based model, with a significant difference (P = 6e-9) between two subgroups and good concordance index (C-index = 0.767), were proven to be robust by external validation. 1530 DEGs including 678 up- and 852 down-regulated genes were identified in the high-risk subgroup S2 compared with the low-risk subgroup S1. Enrichment analyses found five hallmark gene sets were up-regulated while 13 were down-regulated. Then, we found that DNA damage repair pathways were significantly enriched in the S2 subgroup. CNV analysis showed that 30.18% of genes were significantly up-regulated and gene amplification on chromosomes 7 and 8 was significantly elevated in the S2 subgroup. Moreover, enrichment analysis revealed that some DEGs and pathways were associated with immunity. Three tumor-infiltrating immune cell (TIIC) groups with a higher proportion in the S2 subgroup (p = 1e-05, p = 8.7e-06, p = 0.00014) and one TIIC group with a higher proportion in the S1 subgroup (P = 1.3e-06) were identified. Conclusion: We developed a novel, robust classification for understanding PCa relapse. This study validated the effectiveness of deep learning technique in prognosis prediction, and the method may benefit patients and prevent relapse by improving early detection and advancing early intervention.

Circular RNA circPFKP promotes cell proliferation by activating IMPDH2 in prostate cancer.

Prostate cancer (PCa), especially castration-resistant PCa, is a common and fatal disease. circRNAs had been confirmed to affect the proliferation of a variety of malignant tumors. Exploring the role of circRNAs in PCa progression and discovering new therapeutic targets are of great importance for the treatment of PCa. In the present study, we found that the expression of circPFKP was significantly increased in PCa tissues compared with adjacent noncancerous prostate tissues, and was correlated with the D'Amico risk classification, N stage, and prognostic stage group of PCa. CircPFKP promotes the proliferation of PCa cells in vitro and in vivo. Suppressing circPFKP induced the G1/S arrest of PCa cells. Mechanistically, circPFKP interacted with IMPDH2, promoted the biogenesis of guanine nucleotides. Moreover, the replenishment of intracellular guanine nucleotides pool reverses the inhibitory effect of knocking-down circPFKP on PCa cell proliferation. hnRNPF might promote circPFKP generation by binding to flanking Alu elements. Our results identify a novel functional interaction of circPFKP with IMPDH2, which promotes the proliferation of PCa cells.

HNRNPC Promotes Proliferation, Metastasis and Predicts Prognosis in Prostate Cancer.

INTRODUCTION: The incidence of prostate cancer remains high worldwide, while exploring new therapeutic targets for prostate cancer is essential. Heterogeneous nuclear ribonucleoproteins have been proved to regulate tumorigeneses in various cancers. This study aimed to explore the role of HNRNPC in prostate cancer progression. METHODS: HNRNPC expression and its correlation with clinical features and immune infiltration were analyzed by bioinformatics analysis. The effects of HNRNPC on prostate cell proliferation, migration, and invasion were accessed by EdU, colony formation, transwell, and wound-healing assays. RESULTS: The expression level of HNRNPC was significantly increased in prostate cancer tissues and was correlated with the T stage, N stage, Gleason score, PSA level, residual tumors, overall survival, disease-specific survival, and progression-free interval of prostate cancer patients. Silencing HNRNPC inhibited the proliferation and metastasis of prostate cancer cells. The expression of HNRNPC was negatively correlated with the infiltration level of most immune cells in prostate cancer. Mechanistically, HNRNPC may function through regulating gene expression at the posttranscriptional level. CONCLUSION: HNRNPC could be a potential marker for the treatment and prognosis prediction of prostate cancer.

The Emerging Role of Circular RNAs in Prostate Cancer: A Systematic Review.

Prostate cancer is one of the most common malignant tumors that threaten the health of men. It is urgent to explore new molecular targets and develop new drugs for the treatment of prostate cancer. Circular RNAs (circRNAs) are aberrantly expressed in various malignant tumors. The dysregulated circRNAs are involved in the metastasis, tumor growth, drug resistance, and immunosuppression of malignant tumors. The present review systematically summarized publications concerning the biological implications of circRNAs in prostate cancer. The PubMed and Web of Science databases were used to retrieve publications concerning circRNAs and prostate cancer until June 16, 2021. The following keywords were used in the literature search: (circRNA OR circular RNA) AND prostate cancer. 73 publications were enrolled in the present systematic review to summarize the role of circRNAs in prostate cancer. The dysregulated and functional circRNAs were involved in the cell cycle, proliferation, migration, invasion, metastasis, drug resistance and radiosensitivity of prostate cancer. In addition, circRNAs could function through EVs and serve as prognostic and diagnostic biomarkers. Certain circRNAs were correlated with clinicopathological features of prostate cancer. A comprehensive review of the molecular mechanism of the tumorigenesis and progression of prostate cancer may contribute to the development of new therapies of prostate cancer in the future.

Alpha-L-Fucosidase Has Diagnostic Value in Prostate Cancer With "Gray-Zone PSA" and Inhibits Cancer Progression via Regulating Glycosylation.

BACKGROUND: This study aimed to explore the diagnostic value of alpha-l-fucosidase (AFU) in prostate cancer (PCa) patients with "gray-zone PSA" and to investigate the correlation between AFU expression and clinicopathological characteristics of PCa patients. METHODS: The level of AFU and other necessary clinicopathological variables of patients were retrieved from electronic medical records. The transcriptome profiling and clinical information of PCa patients were obtained from The Cancer Genome Atlas (TCGA) database. The protein level of AFU in tissue was assessed by immunohistochemistry (IHC). All the data were processed by appropriate analysis methods. The p-value of <0.05 was considered statistically significant. RESULTS: AFU showed ideal diagnostic value for PCa with prostate-specific antigen (PSA) levels ranging from 4 to 10 ng/ml, and its optimal cutoffs were 19.5 U/L. Beyond this, low AFU expression was associated with high pathological grade, T stage and N stage, more postoperative residual tumors, and poor primary therapy outcome, as well as shorter progression-free interval. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis illustrated that FUCA1/FUCA2 exerted tumor-suppressive function by regulating the glycosylation. CONCLUSIONS: AFU (<19.5 U/L) could effectively distinguish the PCa from the patients with "gray-zone PSA", and low expression of AFU was an independent unfavorable predictor for the clinicopathological characteristics of PCa patients.