An androgen receptor-based signature to predict prognosis and identification of ORC1 as a therapeutical target for prostate adenocarcinoma.

Background: Aberrant activation of androgen receptor (AR) signaling plays a crucial role in the progression of prostate adenocarcinoma (PRAD) and contributes significantly to the development of enzalutamide resistance. In this study, we aimed to identify a novel AR-driven signature that can predict prognosis and endows potentially reveal novel therapeutic targets for PRAD. Methods: The Seurat package was used to preprocess the single-cell RNA sequencing (scRNA-seq). Differentially expressed genes were visualized using limma and pheamap packages. LASSO and multi-variate Cox regression models were established using glmnet package. The package "Consensus Cluster Plus" was utilized to perform the consensus clustering analysis. The biological roles of origin recognition complex subunit 1 (ORC1) in PRAD were determined by gain- and loss-of-function studies in vitro and in vivo. Result: We characterized the scRNA-seq data from GSE99795 and identified 10 AR-associated genes (ARGs). The ARGs model was trained and validated in internal and external cohorts. The ARGs were identified as an independent hazard factor in PRAD and correlated with clinical risk characteristics. In addition, the ARGs were found to be correlated with somatic tumor mutation burden (TMB) levels. Two groups that have distinct prognostic and molecular features were identified through consensus clustering analysis. ORC1 was identified as a critical target among these ARGs, and it ORC1 promoted proliferation and stem-like properties of PRAD cells. Chromatin immunoprecipitation (ChIP)-qPCR assay confirmed that AR could directly bind the promoter of ORC1. Activated AR/ORC1 axis contributed to enzalutamide resistance, and targeting ORC1 rendered PRAD cells more susceptible to enzalutamide. Conclusions: This study defines an AR-driven signature that AR activates ORC1 expressions to promote PRAD progression and enzalutamide resistance, which may provide novel targets for PRAD treatment.

CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway.

Prostate cancer (PCa) endangers the life and health of older men. Most PCa cases develop into castration­resistant PCa (CRPC) within 2 years. At present, the molecular mechanisms of the occurrence and development of PCa and its transformation to CRPC remain unknown. The present study aimed to investigate the role of CKLF­like Marvel transmembrane domain containing family member 5 (CMTM5) in PCa and its molecular mechanism in vitro. PCa tissues and paired adjacent normal prostate tissues from 70 patients were collected to examine the expression levels of CMTM5 and EGFR via immunohistochemistry, reverse transcription­quantitative PCR and western blotting. Then, CMTM5­overexpressing DU145 cells were constructed, and CMTM5 expression in these transfected cells and vector control cells was examined via western blotting. Cell Counting Kit­8 and plate clone formation assays were used to evaluate the proliferation and colony number of CMTM5­overexpressing cells and vector control cells. Then, cell migration and invasion were assessed using wound healing assay, Transwell assay and immunofluorescence analysis with DAPI staining. The effect of CMTM5 on apoptosis and its underlying molecular mechanism were examined using western blotting and flow cytometry. The results demonstrated that CMTM5 expression in PCa tissues and cell lines was significantly downregulated, while EFGR expression was significantly upregulated. The proportion of high CMTM5 expression in PCa tissues was significantly lower compared with that in normal prostate tissues. By contrast, the proportion of high EGFR expression in PCa tissues was significantly increased compared with that in normal prostate tissues. Moreover, CMTM5 overexpression significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis compared with vector control cells in vitro. Furthermore, the regulation of PCa by CMTM5 was associated with the downregulation of PI3K/AKT and its downstream Bcl­2 expression, as well as the upregulation of Bax expression. In conclusion, CMTM5 may be an effective tumor suppressor gene for PCa, especially for castration­resistant PCa, by downregulating EGFR and PI3K/AKT signaling pathway components.

Long-term outcomes of radiofrequency ablation vs. partial nephrectomy for cT1 renal cancer: A meta-analysis and systematic review.

Background: Partial nephrectomy (PN) is one of the most preferred nephron-sparing treatments for clinical T1 (cT1) renal cancer, while radiofrequency ablation (RFA) is usually used for patients who are poor surgical candidates. The long-term oncologic outcome of RFA vs. PN for cT1 renal cancer remains undetermined. This meta-analysis aims to compare the treatment efficacy and safety of RFA and PN for patients with cT1 renal cancer with long-term follow-up of at least 5 years. Method: This meta-analysis was performed following the PRISMA reporting guidelines. Literature studies that had data on the comparison of the efficacy or safety of RFA vs. PN in treating cT1 renal cancer were searched in databases including PubMed, Embase, Web of Science, and the Cochrane Library from 1 January2000 to 1 May 2022. Only long-term studies with a median or mean follow-up of at least 5 years were included. The following measures of effect were pooled: odds ratio (OR) for recurrence and major complications; hazard ratio (HR) for progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Additional analyses, including sensitivity analysis, subgroup analysis, and publication bias analysis, were also performed. Results: A total of seven studies with 1,635 patients were finally included. The treatment efficacy of RFA was not different with PN in terms of cancer recurrence (OR = 1.22, 95% CI, 0.45-3.28), PFS (HR = 1.26, 95% CI, 0.75-2.11), and CSS (HR = 1.27, 95% CI, 0.41-3.95) as well as major complications (OR = 1.31, 95% CI, 0.55-3.14) (P > 0.05 for all). RFA was a potential significant risk factor for OS (HR = 1.76, 95% CI, 1.32-2.34, P < 0.001). No significant heterogeneity and publication bias were observed. Conclusion: This is the first meta-analysis that focuses on the long-term oncological outcomes of cT1 renal cancer, and the results suggest that RFA has comparable therapeutic efficacy with PN. RFA is a nephron-sparing technique with favorable oncologic efficacy and safety and a good treatment alternative for cT1 renal cancer.

Glutathione S-transferase M1 and T1 null genotypes and bladder cancer risk: A meta-analysis in a single ethnic group.

AIM OF STUDY: To further evaluate the influence of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null genotypes on bladder cancer risk, we conducted a meta-analysis in the Chinese population. MATERIALS AND METHODS: PubMed and Chinese databases were electronically searched through April 2016. RESULTS: Nine studies were included for our meta-analysis, involving 1646 bladder cancer cases and 1938 controls. In general, our findings indicated that a significant association existed between GSTM1-null genotype and the risk of bladder cancer in the studied Chinese population (odds ratio = 1.56, 95% confidence interval: 1.36-1.79). However, no significant association between GSTT1 polymorphism and bladder cancer was found. After stratification of the subgroup analyses by source of controls and geographical areas, a substantially elevated risk was revealed between GSTM1-null genotype and bladder cancer in the population-based studies and those conducted in South China and North China. CONCLUSION: Our meta-analysis suggested that GSTM1-null genotype is associated with an increased bladder cancer risk in the Chinese individuals.

A Prospective Randomized Trial Comparing Pneumatic Lithotripsy and Holmium Laser for Management of Middle and Distal Ureteral Calculi.

PURPOSE: The aim of this study was to compare the efficacy and safety between pneumatic and holmium:yttrium-aluminum-garnet (Ho:YAG) laser in the treatment of patients with ureteral stones located in the middle and distal ureter. PATIENTS AND METHODS: We conducted a prospective study in recruiting 982 eligible patients from 2009 to 2012. Patients were randomly divided into two groups-the pneumatic lithotripsy (PL) group or the Ho:YAG laser lithotripsy (LL) group. Patient demographics, stone characteristics, intraoperative parameters, and postoperative complications were evaluated and analyzed. RESULTS: The baseline demographics of patients and stone characteristics were similar in the two groups. The LL group showed significant benefits compared with the PL group in terms of mean operative time (28±9.2 vs 41±12.4 min, P=0.001) and early stone-free rate (80.8% vs 91.3%, P=0.04), but there was no statistically significant difference at the third month (92.6% vs 95.5%, P=0.15). In the LL group, 24 postoperative cases of stricture were seen, whereas only 5 cases occurred in the PL group (P=0.02). The other complications, such as perforation, bleeding, and mucosal injury, were comparable in the two groups. The average postoperative stay was also similar (1.7±2.4 days for PL and 1.5±3.1 days for LL (P=0.62). CONCLUSION: Both PL and LL are effective in the management of middle and distal impacted stones. Ho:YAG laser has advantages in better efficacy of stone fragmentation and a higher early stone-free rate but seems to have to face the increased risks of postoperative stricture.

Long noncoding RNA GHET1 promotes the development of bladder cancer.

In spite of the advances in the diagnosis and treatment of bladder cancer, the prognosis of bladder cancer remains relatively poor. As a result, it is vital to identify novel diagnostic and prognostic marker of bladder cancer. A growing volume of literature has implicated the vital role of long noncoding RNA in the development of cancer. GHET1, a recently identified lncRNA, was initially characterized in gastric cancer. However, its role in bladder cancer remains largely unknown. In this study, we demonstrated that GHET1 was upregulated in bladder cancer tissues compared to adjacent normal tissues and its over-expression correlates with tumor size, advanced tumor and lymph node status, and poor survival. GHET1 knockdown suppressed the proliferation and invasion of bladder cancer cells in vitro. In the meantime, inhibition of GHET1 reversed the epithelial-mesenchymal-transition in bladder cancer cell line. Taken together, our study suggests that the potential use of GHET1 as a prognostic marker and therapeutic target of bladder cancer.