ZNF471 Interacts with BANP to Reduce Tumour Malignancy by Inactivating PI3K/AKT/mTOR Signalling but is Frequently Silenced by Aberrant Promoter Methylation in Renal Cell Carcinoma.

Background: Renal cell carcinoma (RCC) is one of the most common malignant tumours of the urinary system. However, the aetiology and pathogenesis of RCC remain unclear. The C2H2 zinc finger protein (ZNF) family is the largest transcriptional regulatory factor family found in mammals, and Krüppel-associated box domain-containing zinc finger proteins (KRAB-ZFPs) constitute the largest subfamily of the C2H2 zinc finger protein family and play an important role in the occurrence and development of tumours. The aim of this study was to explore the role of abnormal methylation of ZNF471 in the development of renal carcinoma. Methods: In this study, we first used the TCGA and EWAS Data Hub databases to analyse the expression and methylation levels of ZNF471 in renal carcinoma tissues and adjacent normal tissues. Second, we collected samples of renal cancer and adjacent normal tissues at Peking University First Hospital to investigate the expression and methylation level of ZNF471 in renal cancer tissues and the relationships between these levels and the clinicopathological features and prognosis of patients with renal cancer. Next, we investigated the effects of ZNF471 on the proliferation, metastasis, cell cycle progression, and apoptosis of renal cell carcinoma cells by cell biology experiments. Finally, we elucidated the underlying molecular mechanisms of ZNF471 in renal cell carcinoma by transcriptome sequencing, bioinformatics analysis and molecular biology experiments. Results: The expression of ZNF471 in renal carcinoma tissues and cell lines was significantly lower than that in adjacent normal tissues and cell lines due to abnormal promoter CpG methylation. Furthermore, the expression of ZNF471 in renal carcinoma tissues was negatively correlated with tumour stage and grade in patients with renal carcinoma. The results of the cell biology experiments showed that ZNF471 could significantly inhibit the proliferation, migration and cell cycle progression of renal cell carcinoma cells and promote apoptosis in these cells. In addition, ZNF471 could interact with BANP and suppress the malignant phenotype of RCC by inactivating the PI3K/AKT/mTOR signalling pathway. Conclusions: As an important tumour suppressor, ZNF471 can interact with BANP in renal cancer cells and inhibit the activation of the PI3K/AKT/mTOR signalling pathway, thereby inhibiting the occurrence and development of renal cancer.

Novel Androgen Receptor Inhibitors in Non-Metastatic, Castration-Resistant Prostate Cancer: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Enzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications. METHODS: PubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies. RESULTS: Three eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66-0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50-0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0-1.7) and serious AEs (OR, 1.3; 95% CI, 0.99-1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5-3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1-2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4-2.7) and serious AEs (OR, 1.9; 95% CI, 1.3-2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies. CONCLUSIONS: SGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients.

Diagnostic Accuracy of Contemporary Selection Criteria in Prostate Cancer Patients Eligible for Active Surveillance: A Bayesian Network Meta-Analysis.

BACKGROUND: Several active surveillance (AS) criteria have been established to screen insignificant prostate cancer (insigPCa, defined as organ confined, low grade and small volume tumors confirmed by postoperative pathology). However, their comparative diagnostic performance varies. The aim of this study was to compare the diagnostic accuracy of contemporary AS criteria and validate the absolute diagnostic odds ratio (DOR) of optimal AS criteria. METHODS: First, we searched Pubmed and performed a Bayesian network meta-analysis (NMA) to compare the diagnostic accuracy of contemporary AS criteria and obtained a relative ranking. Then, we searched Pubmed again to perform another meta-analysis to validate the absolute DOR of the top-ranked AS criteria derived from the NMA with two endpoints: insigPCa and favorable disease (defined as organ confined, low grade tumors). Subgroup and meta-regression analyses were conducted to identify any potential heterogeneity in the results. Publication bias was evaluated. RESULTS: Seven eligible retrospective studies with 3,336 participants were identified for the NMA. The diagnostic accuracy of AS criteria ranked from best to worst, was as follows: Epstein Criteria (EC), Yonsei criteria, Prostate Cancer Research International: Active Surveillance (PRIAS), University of Miami (UM), University of California-San Francisco (UCSF), Memorial Sloan-Kettering Cancer Center (MSKCC), and University of Toronto (UT). I2 = 50.5%, and sensitivity analysis with different insigPCa definitions supported the robustness of the results. In the subsequent meta-analysis of DOR of EC, insigPCa and favorable disease were identified as endpoints in ten and twenty-two studies, respectively. The pooled DOR for insigPCa and favorable disease were 0.44 (95%CI, 0.31-0.58) and 0.66 (95%CI, 0.61-0.71), respectively. According to a subgroup analysis, the DOR for favorable disease was significantly higher in US institutions than that in other regions. No significant heterogeneity or evidence of publication bias was identified. CONCLUSIONS: Among the seven AS criteria evaluated in this study, EC was optimal for positively identifying insigPCa patients. The pooled diagnostic accuracy of EC was 0.44 for insigPCa and 0.66 when a more liberal endpoint, favorable disease, was used. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/prospero/], PROSPERO [CRD42020157048].