BackgroundTumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines.MethodsTissue 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.ResultsYY1 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.ConclusionsPhase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer–promoter interactions, thereby increasing PCa progression.
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. K E Y W O R D Scomplications, meta-analysis, Renal cell carcinoma, RENAL score, surgical strategiesThis is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
SignificanceProstate cancer (PCa) is a major threat of men's health worldwide, with 20% to 50% patients harboring TP53 mutation. Non-coding RNAs, especially miRNAs, act as crucial regulators in tumor initiation and progression, including PCa. Exploring the leading cause of miRNA abnormal expression and the mechanism of miRNA in PCa tumorigenesis will help the design promising therapeutic approaches. We find that miR-7 is regulated by TP53 gene and inhibits the acidic microenvironment required for tumor formation, thus impacting on histone lactylation. Importantly, in vivo assays demonstrate efficacy of miR-7 on p53-negative tumors, highlighting that miR-7 could be a promising target for development of miRNA-based therapeutics, especially for PCa patients with p53 mutations.
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