MDK promotes M2 macrophage polarization to remodel the tumour microenvironment in clear cell renal cell carcinoma.

The efficacy of immunotherapy for clear cell renal cell carcinoma (ccRCC), especially advanced ccRCC, is limited, presenting a clinical challenge. This limitation is closely tied to the immune regulation network. Understanding the heterogeneity of the tumour microenvironment (TME) is crucial for developing advanced ccRCC therapies. Using publicly available ccRCC data (scRNA-seq, bulk RNA-seq, and somatic mutation data), a multiomics study was performed to explore TME heterogeneity. Three distinct ccRCC immune subtypes were identified through combined scRNA-seq and bulk RNA-seq analysis. A prognostic model based on unique cell signalling molecules in immunosuppressive tumour subtype was validated in the TCGA and CheckMate cohorts. MDK emerged as a critical regulatory gene in the immunosuppressive subtype, predicting a poor ccRCC prognosis and a poor immunotherapy response. MDK promotes M2 macrophage polarization via the MDK-LRP1 interaction, and the inhibition of MDK suppressed M2 polarization. This study revealed the heterogeneity of the ccRCC TME and a reliable prognostic model, shedding light on the vital role of MDK in the immunosuppressive TME and paving the way for optimized ccRCC immunotherapy.

Association between grip strength and stress urinary incontinence of NHANES 2011-2014.

OBJECTIVES: To investigate the association between grip strength (GS) and relative grip strength (rGS) with the prevalence and severity risk of SUI. METHODS: Female patients were retrieved from the NHANES 2011-2014. GS was measured using a digital hand dynamometer, rGS was defined as grip strength divided by BMI. Samples were classified into four groups based on quartiles of GS and rGS distribution (Q1-Q4)。Logistic regression models were established to detect the relationship between GS or rGS and SUI. The potential bias of baseline variables between SUI and non-SUI groups was controlled by performing the propensity score matching (PSM). RESULTS: A total of 4263 samples were included, with 3085 (85%) people in non-SUI group and 1178 (27.6%) people in SUI group. GS and rGS levels of people without SUI were higher than that of SUI patients. Monthly SUI patients' GS and rGS levels were higher than weekly SUI patients' level. Logistic regression analysis showed that risks of prevalence and severity of SUI decreased with increasing levels of GS and rGS. rGS was found to have a stronger association with SUI than GS [prevalence: GS: Q4 vs. Q1: aOR = 0.633, 95%CI = 0.508-0.789, p < 0.001; rGS: Q4 vs. Q1: aOR = 0.365, 95%CI = 0.290-0.459, p < 0.001; severity: GS: Q4 vs. Q1: aOR = 0.727, 95%CI = 0.600-0.881, p = 0.001; rGS: Q4 vs. Q1: aOR = 0.371, 95%CI = 0.282-0.488, p < 0.001]. The results of PSM confirmed that GS and rGS were correlated with SUI. CONCLUSIONS: Lower levels of GS and rGS are associated with an increased prevalence and severity risk of SUI.

YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6.

BACKGROUND: Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines. METHODS: Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid-liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment. RESULTS: YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors. CONCLUSIONS: Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer-promoter interactions, thereby increasing PCa progression.

Development of genomic instability-associated long non-coding RNA signature: A prognostic risk model of clear cell renal cell carcinoma.

Purpose: Renal clear cell carcinoma (ccRCC) is the most lethal of all pathological subtypes of renal cell carcinoma (RCC). Genomic instability was recently reported to be related to the occurrence and development of kidney cancer. The biological roles of long non-coding RNAs (lncRNAs) in tumorigenesis have been increasingly valued, and various lncRNAs were found to be oncogenes or cancer suppressors. Herein, we identified a novel genomic instability-associated lncRNA (GILncs) model for ccRCC patients to predict the overall survival (OS). Methods: The Cancer Genome Atlas (TCGA) database was utilized to obtain full transcriptome data, somatic mutation profiles, and clinical characteristics. The differentially expressed lncRNAs between the genome-unstable-like group (GU) and the genome-stable-like group (GS) were defined as GILncs, with |logFC| > 1 and an adjusted p-value< 0.05 for a false discovery rate. All samples were allocated into GU-like or GS-like types based on the expression of GILncs observed using hierarchical cluster analyses. A genomic instability-associated lncRNA signature (GILncSig) was constructed using parameters of the included lncRNAs. Quantitative real-time PCR analysis was used to detect the in vitro expression of the included lncRNAs. Validation of the risk model was performed by the log-rank test, time-dependent receiver operating characteristic (ROC) curves analysis, and multivariate Cox regression analysis. Results: Forty-six lncRNAs were identified as GILncs. LINC00460, AL139351.1, and AC156455.1 were employed for GILncSig calculation based on the results of Cox analysis. GILncSig was confirmed as an independent predictor for OS of ccRCC patients. Additionally, it presented a higher efficiency and accuracy than other RCC prognostic models reported before. Conclusion: GILncSig score was qualified as a critical indicator, independent of other clinical factors, for prognostic prediction of ccRCC patients.

Transgenic construction and functional miRNA analysis identify the role of miR-7 in prostate cancer suppression.

Although miR-7 suppresses the initiation and progression in cancers, little is known about its role in prostate cancer, especially in transgenic mouse models. In present study, we found that expression of miR-7, regulated by p53, was lower in prostate cancer tissues, and miR-7 overexpression significantly mitigated prostate cancer cells growth both in vitro, in organoids and in vivo regardless of p53 status. After we generated miR-7 overexpression transgenic mice and miR-7+/TRAMP mice, we found that transgenic overexpression of miR-7 in mice is safe and miR-7+/TRAMP mice have a preferred overall survival. Moreover, in vivo treatment of miR-7 inhibited subcutaneous tumour growth in mice and prolonged the survival of mice harboring prostate cancer lung metastasis when co-injection with PD-1 antibody. In addition, miR-7 downregulated glycolysis of prostate cancer cells by inhibiting several key pathways including HIF-1α, and subsequently remodeled acidic tumour microenvironment, PanKLa level and T cell infiltration. In summary, our findings highlighted a promising target for development of miRNA-based therapeutics for prostate cancer patients regardless of p53 status.

The value of renal score in both determining surgical strategies and predicting complications for renal cell carcinoma: A systematic review and meta-analysis.

OBJECTIVES: Radical nephrectomy (RN) was the standard treatment for renal cell carcinoma (RCC). However, recent studies have found that partial nephrectomy (PN) could achieve similar effects as radical nephrectomy, and has the advantages of less bleeding and shorter hospital stay. The choice of surgical strategies has become a concern of clinicians, which could be guided by renal score introduced by Kutikov et al Therefore, we conducted this meta-analysis to clarify the value of renal score of determining surgical strategies and predicting complications. METHODS: The keywords "RENAL score," "renal nephrometry score," or "nephrometry score" were used to retrieve electronic databases for relevant literature up to Feb 2020, including PubMed, Web of Science, and the Cochrane library. Surgical strategies and complications are outcome measures. Risk ratio (RR) with 95% confidence intervals (CI) is applied to assess the effect size. RESULTS: A total of 20 studies met the selection criteria for meta-analysis. There was significant difference in RN operation rate for each subgroup (low-moderate: RR = 3.50, 95% Cl = 2.60-4.71, P < .001; low-high: RR = 6.29, 95% Cl = 4.40-9.00, P < .001; moderate-high: RR = 1.80, 95% Cl = 1.39-2.32, P < .001).The overall incidence of complications from high renal score group was significantly higher than that in low renal score group (low-moderate: RR = 1.32, 95% Cl = 1.03-1.69, P = .026; low-high: RR = 2.45, 95% Cl = 1.48-4.07, P = .001; moderate-high: RR = 1.75, 95% Cl = 1.17-2.61, P = .007). CONCLUSIONS: This meta-analysis indicated that renal score is an efficient tool for determining surgical strategies and predicting complications in PN. More prospective research is essential to verify the predictive value of renal score.