MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis.

Emerging evidence has highlighted that dysregulation of lipid metabolism in clear cell renal cell carcinoma (ccRCC) is associated with tumor development and progression. HIF-2α plays an oncogenic role in ccRCC and is involved in abnormal lipid accumulation. However, the underlying mechanisms between these two phenomena remain unknown. Here, MED15 was demonstrated to be a dominant factor for HIF-2α-dependent lipid accumulation and tumor progression. HIF-2α promoted MED15 transcriptional activation by directly binding the MED15 promoter region, and MED15 overexpression significantly alleviated the lipid deposition inhibition and malignant tumor behavior phenotypes induced by HIF-2α knockdown. MED15 was upregulated in ccRCC and predicted poor prognosis. MED15 promoted lipid deposition and tumor progression in ccRCC. Mechanistic investigations demonstrated that MED15 acts as SREBP coactivator directly interacting with SREBPs to promote SREBP-dependent lipid biosynthesis enzyme expression, and promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis. Overall, we describe a molecular regulatory network that links MED15 to lipid metabolism induced by the SREBP pathway and the classic HIF-2α pathway in ccRCC. Efforts to target MED15 or inhibit MED15 binding to SREBPs as a novel therapeutic strategy for ccRCC may be warranted.

High Hepcidin expression predicts poor prognosis in patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a growing public health challenge worldwide. Hepcidin antimicrobial peptide (HAMP) is differentially expressed in various tumors. However, the roles and functions of HAMP in ccRCC remain unclear. In the present study, we integrated systematic bioinformatics approaches to investigate the roles and functions of HAMP and its association with immune cell infiltration in ccRCC. Compared with paracancerous tissue, HAMP expression was significantly upregulated in ccRCC patients. Meanwhile, we found good diagnostic performance of HAMP for ccRCC patients and its close associations with the clinicopathological features of ccRCC patients. In addition, we found that HAMP is closely related to multiple immune pathways and positively correlated with various immune cells. HAMP was a significant independent predictor for ccRCC. High expression of HAMP was associated with worse clinical prognosis and more immune cell infiltration in ccRCC patients. HAMP may offer potential as a biomarker to predict prognosis and the clinical treatment outcome of ccRCC patients.

CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation.

BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease that is characterized by infiltrating inflammatory cells in the prostate and pelvic or by perineal pain. Receptor CXCR3modulates immune and inflammatory responses; however, the effects of CXCR3 antagonist AMG487 in the context of CP/CPPS are unknown. Therefore, we investigated the effect of AMG487 in experimental autoimmune prostatitis (EAP) mice and explored the potential functional mechanisms. METHODS: The EAP model was induced by intradermally injecting a mixture of prostate antigens and complete Freund's adjuvant on Days 0 and 28. To evaluate the effect of AMG487 on EAP mice, treatment with AMG487 and vehicle solution was conducted for the indicated period. Then, procedures were performed, including behavioral test, to evaluate the pain response to stimulation before the mice were killed and a histological assessment to evaluate the inflammation after the mice were killed. Immunofluorescence, flow cytometry, and Western blot assay were used to analyze the functional phenotype and regulation mechanism of AMG487 on T helper type 1 (Th1) cells and macrophages. RESULTS: We found high expression of CXCR3 in human benign prostate tissues with inflammation and EAP mice. The elevated CXCR3 in prostate tissues correlates with the severity of inflammation. CXCR3 antagonist AMG487 treatment ameliorated the inflammatory changes and the pelvic pain of EAP mice. AMG487 inhibits Th1 cell differentiation through the IL-12/STAT4pathway and inhibits pro-inflammatory M1 macrophages through the lipopolysaccharide/NF-κB p65signaling. AMG487 could inhibit the secretion of inflammatory mediators in EAP mice. CONCLUSION: CXCR3 antagonist AMG487 could ameliorate the inflammatory changes and the pelvic pain of EAP mice by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation. Thus, the results imply that AMG487 has the potential as an effective therapeutic agent in the prevention and treatment of EAP.

PKMYT1, exacerbating the progression of clear cell renal cell carcinoma, is implied as a biomarker for the diagnosis and prognosis.

Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urological malignancies with high tumor heterogeneity, and reliable biomarkers are still needed for its diagnosis and prognosis. WEE family kinases function as key regulators of the G2/M transition, have essential roles in maintaining cellular genomic stability and have the potential to be promising therapeutic targets in various tumors. However, the roles of WEE family kinases in ccRCC remain undetermined. In the present study, we first explored multiple public datasets and found that PKMYT1 was up-regulated in both RCC tumors and cell lines. Expression levels of PKMYT1 were highly associated with pathological stage and grade. Kaplan-Meier curves showed that high PKMYT1 expression was associated with lower overall survival and disease-free survival. Receiver operating characteristic curves revealed that the expression of PKMYT1 could better distinguish ccRCC from normal samples. Functional enrichment analysis demonstrated that cell cycle- related pathways and epithelial to mesenchymal transition (EMT) might be potential mechanisms of PKMYT1 in ccRCC tumorigenesis. Moreover, knockdown of PKMYT1 in vitro attenuated the proliferation, migration and invasion of RCC cell lines, promoted cell apoptosis and prevented the EMT phenotype in vitro. In conclusion, our study demonstrated that PKMYT1 has the potential to act as a diagnostic and prognostic biomarker for RCC patients. Targeting PKMYT1 may be considered as a new potential therapeutic method and direction in RCCs.

Pathogenic Roles of CXCL10 in Experimental Autoimmune Prostatitis by Modulating Macrophage Chemotaxis and Cytokine Secretion.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease characterized by intraprostatic leukocyte infiltration and pelvic or perineal pain. Macrophages play vital roles in the pathogenesis of CP/CPPS. However, the mechanisms controlling the activation and chemotaxis of macrophages in CP/CPPS remain unclear. This study aimed to investigate the roles of the CXCL10/CXCR3 pathway in the activation and chemotaxis of macrophages in CP/CPPS patients. The serums of CP/CPPS patients and healthy volunteers were collected and measured. Results showed that CXCL10 expression was significantly elevated and correlated with the severity of CP/CPPS patients. The experimental autoimmune prostatitis (EAP) model was generated, and adeno-associated virus and CXCR3 inhibitors were used to treat EAP mice. Immunofluorescence, flow cytometry, and Western blotting were used to analyze the functional phenotype and regulation mechanism of macrophages. Results showed that CXCL10 deficiency ameliorates EAP severity by inhibiting infiltration of macrophages to prostate. Moreover, CXCL10 could induce macrophage migrations and secretions of proinflammatory mediators via CXCR3, which consequently activated the downstream Erk1/2 and p38 MAPK signaling pathways. We also showed that prostatic stromal cell is a potential source of CXCL10. Our results indicated CXCL10 as an important mediator involved in inflammatory infiltration and pain symptoms of prostatitis by promoting the migration of macrophages and secretion of inflammatory mediators via CXCR3-mediated ERK and p38 MAPK activation.

A costimulatory molecule-related signature in regard to evaluation of prognosis and immune features for clear cell renal cell carcinoma.

Costimulatory molecules have been proven to enhance antitumor immune responses, but their roles in clear cell renal cell carcinoma (ccRCC) remain unexplored. In this study, we aimed to explore the gene expression profiles of costimulatory molecule genes in ccRCC and construct a prognostic signature to improve treatment decision-making and clinical outcomes. We performed the first comprehensive analysis of costimulatory molecules in patients with ccRCC and identified 13 costimulatory molecule genes with prognostic values and diagnostic values. Consensus clustering analysis based on these 13 costimulatory molecular genes showed different distribution patterns and prognostic differences for the two clusters identified. Then, a costimulatory molecule-related signature was constructed based on these 13 costimulatory molecular genes, and validated in an external dataset, showing good performance for predicting a patient's prognosis. The signature was an independent risk factor for ccRCC patients and was significantly correlated with patients' clinical factors, which could be used as a complement for clinical factors. In addition, the signature was associated with the tumor immune microenvironment and the response to immunotherapy. Patients identified as high-risk based on our signature exhibited a high mutation frequency, a high level of immune cell infiltration, and an immunosuppressive microenvironment. High-risk patients tended to have high cytolytic activity scores and immunophenoscore of CTLA4 and PD1/PD-L1/PD-L2 blocker than low-risk patients, suggesting these patients may be more suitable for immunotherapy. Therefore, our signature could provide clinicians with prognosis predictions and help guide treatment for ccRCC patients.

Identification of a Costimulatory Molecule-Related Signature for Predicting Prognostic Risk in Prostate Cancer.

Costimulatory molecules have been proven to enhance antitumor immune responses, but their roles in prostate cancer (PCa) remain unexplored. In this study, we aimed to explore the gene expression profiles of costimulatory molecule genes in PCa and construct a prognostic signature to improve treatment decision making and clinical outcomes. Five prognosis-related costimulatory molecule genes (RELT, TNFRSF25, EDA2R, TNFSF18, and TNFSF10) were identified, and a prognostic signature was constructed based on these five genes. This signature was an independent prognostic factor according to multivariate Cox regression analysis; it could stratify PCa patients into two subgroups with different prognoses and was highly associated with clinical features. The prognostic significance of the signature was well validated in four different independent external datasets. Moreover, patients identified as high risk based on our prognostic signature exhibited a high mutation frequency, a high level of immune cell infiltration and an immunosuppressive microenvironment. Therefore, our signature could provide clinicians with prognosis predictions and help guide treatment for PCa patients.

IL-6/STAT3 pathway is involved in the regulation of autophagy in chronic non-bacterial prostatitis cells, and may be affected by the NLRP3 inflammasome.

Studies have shown that the cytokine IL-6 plays an important role in the occurrence and development of chronic non-bacterial prostatitis (CNP), but the specific mechanism by which this cytokine regulates CNP is still unclear. At the same time, relevant research have also shown that autophagy is involved in regulating the occurrence and development of inflammation. The possible mechanisms are IL-6/STAT3 signaling pathway and NLRP3 inflammasome. On the basis of establishing the CNP model in rats, we found that IL-6 can regulate autophagy of CNP cells and is associated with the STAT3 pathway and NLRP3 inflammasome. Our results indicate that IL-6 is involved in the regulation of autophagy signaling pathways in CNP. IL-6/STAT3 signaling pathway can suppress cell autophagy pathway in CNP; And the NLRP3 inflammasome may regulate CNP cell autophagy by regulating the IL-6/STAT3 pathway. These findings may provide a new theoretical basis for the pathogenesis of CNP, as well as new ideas and new targets for the treatment and prevention of CNP.

Comparison of Therapeutic Effects Among Different Surgical Approaches in Robot-Assisted Partial Nephrectomy: A Systematic Review and Meta-Analysis.

Purpose: To systematically explore the superiority of the transperitoneal approach in robot-assisted partial nephrectomy (TP-RAPN) and retroperitoneal approach in robot-assisted partial nephrectomy (RP-RAPN). Methods: Several databases were searched including PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, CBM, Wan Fang, and VIP to identify relevant studies that reported the comparison of the TP-RAPN and RP-RAPN. Outcomes of data were pooled and analyzed with Review Manager 5.3 to compare the intraoperative and postoperative variables and postoperative complications. Based on the heterogeneity of the studies, odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated using a random-effect model or fixed-effect model. The sensitivity analysis and the subgroup analysis were used to minimize the effects of heterogeneity. And, publication bias was assessed by funnel plots. Results: In all, 16 studies met the inclusion criteria, including 2336 TP-RAPN patients and 1705 RP-RAPN patients. This meta-analysis reviewed 16 studies on RAPN, and the RP-RAPN showed shorter operative time (OT) (WMD 13.18 minutes; 95% CI 5.04-21.31; p = 0.001), shorter postoperative bowel function recovery (WMD 1.97 days; 95% CI 0.43-3.52; p = 0.01), shorter length of stay (LOS) (WMD 0.51 days; 95% CI 0.25-0.77; p = 0.0001), and lower estimated blood loss (EBL) (WMD 7.08 mL; 95% CI 1.41-12.74; p = 0.01) than the TP-RAPN. Additionally, no significant differences were found in other outcomes. Conclusions: In comparison, the RP-RAPN had significantly shorter OT, postoperative bowel function recovery time, LOS, and lower EBL. The RP-RAPN is associated with better value for posterior and laterally located tumors and is faster and equally safe and low costs for the patient.

Integrated analysis of the functions of RNA binding proteins in clear cell renal cell carcinoma.

RNA binding proteins (RBPs) dysregulation is involved in the processes of various tumors. However, the roles of RBPs in clear cell renal cell carcinoma (ccRCC) remain poorly understand. In present study, we first performed consensus clustering and identified two clusters, of which cluster 2 was closely correlated with the malignancy of ccRCC. Differentially expressed RBPs between normal and tumor tissues were obtained, comprising 71 up-regulated and 44 down-regulated ones. Then, ten hub genes were selected and validated using The Human Protein Atlas database and receiver operating characteristic curves, showing good diagnostic value for cancers. Besides, we identified ten RBPs with the most useful prognostic values, and were used to construct a risk score model. The model could be used to stratify patients with different prognosis and phenotype distributions. The model showed good performance and can be used as a complementation for clinical factors to guide clinical practice in the future.

Effects of RNA Binding Proteins on the Prognosis and Malignant Progression in Prostate Cancer.

Prostate cancer (PCa) is a common lethal malignancy in men. RNA binding proteins (RBPs) have been proven to regulate the biological processes of various tumors, but their roles in PCa remain less defined. In the present study, we used bioinformatics analysis to identify RBP genes with prognostic and diagnostic values. A total of 59 differentially expressed RBPs in PCa were obtained, comprising 28 upregulated and 31 downregulated RBP genes, which may play important roles in PCa. Functional enrichment analyses showed that these RBPs were mainly involved in mRNA processing, RNA splicing, and regulation of RNA splicing. Additionally, we identified nine RBP genes (EXO1, PABPC1L, REXO2, MBNL2, MSI1, CTU1, MAEL, YBX2, and ESRP2) and their prognostic values by a protein-protein interaction network and Cox regression analyses. The expression of these nine RBPs was validated using immunohistochemical staining between the tumor and normal samples. Further, the associations between the expression of these nine RBPs and pathological T staging, Gleason score, and lymph node metastasis were evaluated. Moreover, these nine RBP genes showed good diagnostic values and could categorize the PCa patients into two clusters with different malignant phenotypes. Finally, we constructed a prognostic model based on these nine RBP genes and validated them using three external datasets. The model showed good efficiency in predicting patient survival and was independent of other clinical factors. Therefore, our model could be used as a supplement for clinical factors to predict patient prognosis and thereby improve patient survival.