RNF7 inhibits apoptosis and sunitinib sensitivity and promotes glycolysis in renal cell carcinoma via the SOCS1/JAK/STAT3 feedback loop.

BACKGROUND: RING finger protein 7 (RNF7) is a highly conserved protein that functions as an E3 ubiquitin ligase. RNF7 overexpression is indicated in multiple human cancers, but its role in renal cell carcinoma (RCC) and the mechanisms underlying how it regulates the initiation and progression of RCC have not been explored. METHODS: Bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction (RT-PCR), and Western blot were conducted to determine the expression of RNF7 in RCC tissues and cell lines. Knockdown and overexpression experiments were performed to examine the effects of RNF7 on cell viability, apoptosis, and glycolysis in vitro and on tumor growth in nude mice in vivo. RESULTS: The elevated RNF7 expression in tumor tissues of patients with RCC was correlated with poor survival. RNF7 overexpression inhibited apoptosis and promoted glycolysis in vitro and increased tumor growth in vivo by activating the JAK/STAT3 signaling pathway by ubiquitination of SOCS1. Moreover, RNF7 overexpression affected the sensitivity of RCC cells to sunitinib. Finally, STAT3 activation was necessary for transcriptional induction of RNF7. CONCLUSION: These results demonstrate that RNF7 inhibited apoptosis, promoted glycolysis, and inhibited sunitinib sensitivity in RCC cells via ubiquitination of SOCS1, thus activating STAT3 signaling. These suggest the potential for targeting the RNF7-SOCS1/JAK/STAT3 pathway for RCC treatment.

TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway.

BACKGROUND: The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. METHODS: The mRNA levels of TRIM27 and Kaplan-Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. RESULTS: We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. CONCLUSIONS: Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

Complete transperitoneal laparoscopic nephroureterectomy in a single position for upper urinary tract urothelial carcinoma and comparative outcomes.

BACKGROUND: To describe the techniques and outcomes of complete transperitoneal laparoscopic nephroureterectomy (CTLNU) for upper urinary tract urothelial carcinoma (UTUC) in a single position. MATERIALS AND METHODS: Those patients with localized UTUC were included, among which 50 cases had CTLNU while 48 cases had laparoscopic nephroureterectomy with open bladder cuff excision (LNOBE). The clinical data were collected and analyzed retrospectively. RESULTS: All 98 patients underwent successful procedures of radical nephroureterectomy without transferring into open surgery. No significant difference was found among baseline clinical characteristics. Compared with the LNOBE group, the CTLNU group had a shorter operative time (98.5±40.3 min vs. 132.4±60.2 min), less blood loss (60.4±20.3 ml vs. 150.6±50.2 ml), shorter length of hospital stay (5.3±2.2 days vs. 8.1±2.3 days), and shorter incision (6.3±1.2 cm vs. 11.5±3.2 cm). The disease-related outcomes such as pathological stage, tumor grade, and recurrence rate were similar between the two groups. CONCLUSIONS: The CTLNU in a single position had advantages of shorter operation time, less blood loss, and shorter incision length. This surgical technique is a more minimally invasive, simplified, and effective way to perform the radical nephroureterectomy.

Excavation of diagnostic biomarkers and construction of prognostic model for clear cell renal cell carcinoma based on urine proteomics.

Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common pathology type in kidney cancer. However, the prognosis of advanced ccRCC is unsatisfactory. Thus, early diagnosis becomes one of the most important research priorities of ccRCC. However, currently available studies about ccRCC lack urine-related further studies. In this study, we applied proteomics to search urinary biomarkers to assist early diagnosis of ccRCC. In addition, we constructed a prognostic model to assist judge patients' prognosis. Materials and methods: Urine which was used to perform 4D label-free quantitative proteomics was collected from 12 ccRCC patients and 11 non-tumor patients with no urinary system diseases. The urine of 12 patients with ccRCC confirmed by pathological examination after surgery was collected before operatoin. Bioinformatics analysis was used to describe the urinary proteomics landscape of these patients with ccRCC. The top ten proteins with the highest expression content were selected as the basis for subsequent validation. Urine from 46 ccRCC patients and 45 control patients were collected to use for verification by enzyme linked immunosorbent assay (ELISA). In order to assess the prognostic value of urine proteomics, a prognostic model was constructed by COX regression analysis on the intersection of RNA-sequencing data in The Cancer Genome Atlas (TCGA) database and our urine proteomic data. Results: 133 proteins differentially expressed in the urinary samples were found and 85 proteins (Fold Change, FC>1.5) were identified up-regulated while 48 down-regulated (FC<0.5). Top 10 proteins including S100A14, PKHD1L1, FABP4, ITIH2, C3, C8G, C2, ATF6, ANGPTL6, F13B were performed ELISA to verify. The results showed that PKHD1L1, ANGPTL6, FABP4 and C3 were statistically significant (P<0.05). We performed multivariate logistic regression analysis and plotted a nomogram. Receiver operating characteristic (ROC) curve indicted that the diagnostic efficiency of combined indicators is satisfactory (Aare under curve, AUC=0.835). Furthermore, the prognostic value of the urine proteomics was explored through the intersection between urine proteomics and TCGA RNA-seq data. Thus, COX regression analysis showed that VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 were statistically significant (P<0.05). Conclusion: Our study indicated that the application of urine proteomics to explore diagnostic biomarkers and to construct prognostic models of renal clear cell carcinoma is of certain clinical value. PKHD1L1, ANGPTL6, FABP4 and C3 can assist to diagnose ccRCC. The prognostic model constituted of VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 can significantly predict the prognosis of ccRCC patients, but this still needs more clinical trials to verify.

Integrative analysis of transcriptomic landscape and urinary signature reveals prognostic biomarkers for clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT) have poor prognosis. We aimed to reveal features of ccRCC with VTT and develop a urine-based prognostic classifier to predict ccRCC prognosis through integrative analyses of transcriptomic landscape and urinary signature. Methods: RNA sequencing was performed in five patients with ccRCC thrombus-tumor-normal tissue triples, while mass spectrometry was performed for urine samples from 12 ccRCC and 11 healthy controls. A urine-based classifier consisting of three proteins was developed to predict patients' survival and validated in an independent cohort. Results: Transcriptomic analysis identified 856 invasion-associated differentially expressed genes (DEGs). Furthermore, proteomic analysis showed 133 differentially expressed proteins (DEPs). Integration of transcriptomic landscape and urinary signature reveals 6 urinary detectable proteins (VSIG4, C3, GAL3ST1, TGFBI, AKR1C3, P4HB) displaying abundance changes consistent with corresponding genes in transcriptomic profiling. According to TCGA database, VSIG4, TGFBI, and P4HB were significantly overexpressed in patients with shorter survival and might be independent prognostic factors for ccRCC (all p<0.05). A prognostic classifier consisting of the three DEPs highly associated with survival performed satisfactorily in predicting overall survival (HR=2.0, p<0.01) and disease-free survival (HR=1.6, p<0.001) of ccRCC patients. The ELISA analysis of urine samples from an independent cohort confirmed the satisfied predictive power of the classifier for pathological grade (AUC=0.795, p<0.001) and stage (AUC=0.894, p<0.001). Conclusion: Based on integrative analyses of transcriptomic landscape and urinary signature, the urine-based prognostic classifier consisting of VSIG4, TGFBI, and P4HB has satisfied predictive power of ccRCC prognosis and may facilitate ccRCC molecular subtyping and treatment.

Association between testosterone and cancers risk in women: a two-sample Mendelian randomization study.

OBJECTIVE: Previous observational studies have explored the correlation between testosterone and cancer risk. However, the causal association between testosterone and various cancer types in women remains inconclusive. The objective of this Mendelian randomization study is to evaluate the causal links between total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in females. METHODS: Initially, a rigorous quality control process was employed to identify suitable instrumental single nucleotide polymorphisms (SNPs) associated with the exposure under investigation that exhibited a significant association. The genetic causal relationship between female testosterone levels and the risk of developing cancers was examined through a two-sample Mendelian randomization. Various analytical methods, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were applied in the investigation. Key findings were primarily based on the results obtained via IVW (random effects), and sensitivity analyses were conducted to assess the reliability of the obtained results. Furthermore, maximum likelihood, penalized weighted median, and IVW (fixed effects) methods were utilized to further validate the robustness of the results. RESULTS: Based on the results of IVW analysis, our study indicated a positive causal relationship between BT and breast cancer (OR = 1.1407, 95%CI: 1.0627-1.2244, P = 0.0015) and endometrial cancer (OR = 1.4610, 95%CI: 1.2695-1.6813, P = 1.22E-06). Moreover, our findings also showed a positive causal association between TT and breast cancer (OR = 1.1764, 95%CI: 1.0846-1.2761, P = 0.0005), cervical cancer(OR = 1.0020, 95%CI: 1.0007-1.0032, P = 0.0077), and endometrial cancer(OR = 1.4124, 95%CI: 1.2083-1.6511, P = 0.0001). Additionally, our results demonstrated a negative causal relationship between BT and ovarian cancer (OR = 0.8649, 95%CI: 0.7750-0.9653, P = 0.0320). However, no causal relationship was found between BT, TT and other types of cancer (corrected P > 0.05). CONCLUSIONS: This study elucidates the role of testosterone on the development of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. It also hints at a potential but fragile link between testosterone and bladder cancer, as well as thyroid cancer. Nonetheless, it's worth noting that no statistically significant relationship between testosterone and various other types of cancer in females was identified.

Trans-retro-peritoneal laparoscopic partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

Background: Urologists still encounter challenges when it comes to the surgical management of tumors located on the posterior lip and posterior renal hilar region. We propose a trans-retro-peritoneal (TRP) technique to address the difficulties associated with posterior hilar tumors during retroperitoneal laparoscopic partial nephrectomy (LPN). Its efficacy was evaluated in a retrospective case-control study. Methods: The patients with posterior hilar tumors (≤7 cm) that underwent retroperitoneal LPN were included. The TRP technique allowed the posterior hilar tumor completely visible by incising the ventral peritoneum and rotating kidney ventrally during retroperitoneal LPN, which was applied in 36 cases, while the conventional retroperitoneal LPN was performed in 22 cases. Perioperative data were analyzed to evaluate the efficacy of TRP-LPN. Results: In TRP-LPN group, the TRP technique was successfully performed in all the patients without converting to open surgery or radical nephrectomy. The warm ischemia time was significantly shorter in TRP-LPN group than conventional LPN group (20.3 vs. 28.5 min, P<0.001). Furthermore, the mean estimated blood loss in TRR-LPN group was significantly less than that in conventional LPN group (86.5 vs. 90.9 mL, P<0.05). The mean operation time and recovery time of gastrointestinal function were similar between two groups. No severe complications occurred, and no positive surgical margin was found. The rate of Trifecta achievement was 50.0% (18/36) and 31.8% (7/22) respectively for TRP-LPN and conventional LPN (P=0.175). After mean follow-up of 21 months, no recurrence or metastasis occurred in all cases. Conclusions: Our findings, as demonstrated by the Trifecta outcomes, support the feasibility and efficacy of TRP-LPN in managing posterior renal hilar tumors. This approach may be considered as an efficient option for surgical management of such tumors.

Value of digital rectal examination in patients with suspected prostate cancer: a prospective cohort analysis study.

Background: Digital rectal examination (DRE) is a straightforward, cost-effective, practical, and time-honored physical examination method that plays a valuable role in the detection of prostate cancer (PCa). Nevertheless, with the advent of the prostate-specific antigen (PSA) era, the necessity of performing DRE has become a subject of debate. Our aim was to investigate the diagnostic efficacy and adjunctive role of DRE in a population (Prostate Imaging Reporting and Data System (PI-RADS), PI-RADS ≥3 or PSA ≥4 ng/mL) suspected of PCa. Methods: Five hundred and ninety-seven patients with suspected PCa requiring referral for biopsy were prospectively enrolled consecutively from February 2020 to May 2021. All patients received DRE and corresponding clinical diagnosis by a urologist before biopsy. According to the collected clinical and pathological information, the diagnostic performance of DRE in different PSA stratifications, and its association with tumor location and Gleason score (GS) were statistically analyzed. Results: Among patients with suspected cancer, the diagnostic accuracy of DRE was 63.45%. Compared with central zone or transition zone tumors, the recall rate of peripheral zone PCa with DRE-positive results was higher (65.50% vs. 34.55%). DRE-positive results were significantly correlated with GS ≥7 PCa (P<0.001), and the average GS of DRE-positive PCa patients was significantly higher than that of DRE-negative (7.92 vs. 7.11, P<0.001). Conclusions: DRE may help physicians further judge the necessity of biopsy in patients with elevated PSA, and preliminarily estimate the location and invasiveness of the tumor. However, it is still necessary to explore the value of DRE in a normal PSA population.

Lipid-Poor Renal Angiomyolipoma Mimicking Renal Cell Carcinoma on 68 Ga-FAPI-04 PET/CT.

ABSTRACT: FAPI PET/CT findings of renal tumors have been rarely reported. We describe 68 Ga-FAPI-04 PET/CT findings in 1 case with lipid-poor renal angiomyolipoma and 1 case with high-grade clear cell renal cell carcinoma. Both tumors showed intense 68 Ga-FAPI-04 uptake. These 2 cases indicate that lipid-poor renal angiomyolipoma should be included in the differential diagnosis of FAPI-avid renal tumors.

A genomic mutation spectrum of collecting duct carcinoma in the Chinese population.

BACKGROUND: Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population. METHODS: Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts. RESULTS: Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, including RBM14, MTUS1, GAK, DST, RNF213 and XIRP2 (20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes, SETD2 was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA); CDKN2A was a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note, CDKN2A (CNV alteration: 30%, 3 of 10) and CDKN2A-AS1 were the only overlapping genes of these four cohorts. Importantly, the CDKN2A mutation in our cohort differed from previous studies in urinary carcinomas. Moreover, CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was the CDKN2A-mediated p53/RB1 pathway. CONCLUSIONS: Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The altered CDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.

Sustainable functional urethral reconstruction: Maximizing early continence recovery in robotic-assisted radical prostatectomy.

OBJECTIVE: To evaluate the safety profile and short-term functional outcome of sustainable functional urethral reconstruction (SFUR) in robotic-assisted radical prostatectomy (RARP). METHODS: One hundred and sixty-two consecutive prostate cancer patients who underwent RARP were retrospectively analyzed, in which 53 had undergone SFUR while the other 109 had undergone conventional RARP procedures. Immediate, 2-week, 1-month and 3-month continence recovery and other perioperative data were compared to evaluate short-term surgical and functional outcome. RESULTS: The median age was 68 and 67 years in the experimental group and control group, respectively (p=0.206), with a median prostate-specific antigen (PSA) of 13.6 ng/mL (interquartile range [IQR], 8.46-27.32 ng/mL) in the experimental group and 13.84 ng/mL (IQR, 9.12-26.80 ng/mL) in control group (p=0.846). Immediate, 2-week, 1-month and 3-month continence recovery rates between the groups were 34.0% vs. 3.7%, 50.9% vs. 14.7%, 62.3% vs. 27.5%, and 79.2% vs. 63.3% (all p<0.05). The morphological changes made by the new reconstruction technique were maintained on magnetic resonance imaging (MRI) 3 months postoperatively. Nerve-sparing procedures and adoption of the new reconstruction technique were significantly relevant to continence recovery on logistics regression model (p<0.001). CONCLUSIONS: SFUR is a safe and easy-to-handle modification that may contribute to early continence return for RARP. Long-term follow-up and prospective studies are required to further evaluate its value in postoperative quality-of-life improvement.

Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer.

PURPOSE: Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer. EXPERIMENTAL DESIGN: The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer. RESULTS: Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6- cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model. CONCLUSIONS: OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.

Overexpression of long non­coding RNA n346372 in bladder cancer tissues is associated with a poor prognosis.

Accumulating evidence has confirmed that dysregulated long non­coding RNAs (lncRNAs) participate in the initiation and progression of a number of solid tumors and have potential applications for early diagnosis, targeted therapy, and the prognosis of patients with bladder cancer. In the present study, via high­throughput sequencing technology and bioinformatics analysis, a total of 169 lncRNAs with significantly differential expression between bladder cancer tissues and paired adjacent normal tissues (n=10) were initially identified by screening. Reverse­transcription­quantitative polymerase chain reaction was carried out to validate the expression levels of lncRNA­n346372 in 60 pairs of tissue samples from bladder cancer patients. The results indicated that lncRNA­n346372 was upregulated in bladder cancer tissues compared with the matched adjacent normal tissues (P<0.05). In addition, the results of fluorescence in situ hybridization analysis of bladder cancer cells and tissues demonstrated that lncRNA­n346372 is located in the cytoplasm, and the expression of lncRNA­n346372 in bladder cancer tissues was significantly increased compared with the paired normal tissues. Following a χ2 test with common clinical variables among the patients, the expression level of lncRNA­n346372 was demonstrated to be positively associated with advanced tumor stage and poor histological differentiation of bladder cancer. Kaplan­Meier survival analysis revealed that patients with high expression of n346372 were more likely to have a poor prognosis compared with patients with low n346372 expression. Finally, univariate and multivariate analyses indicated that the relative level of n346372, apart from tumor stage and histological grade, may serve as an independent prognostic factor of bladder cancer. To the best of the authors' knowledge, this is the first study to verify the dysregulated expression of lncRNA­n346372 in bladder cancer; an association of this lncRNA with overall survival of bladder cancer patients was also uncovered in the present study, suggesting that lncRNA­n346372 may contribute to the initiation and/or progression of bladder cancer with potential applications in the clinic.