Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel–Lindau ( VHL ) tumor-suppressor gene. However, it is still not clear how mutations in VHL , encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor-α (HIFα), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (EC), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between VHL -deficient renal tubule cells and the ECs, and the activated ECs in turn induced macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by VHL -deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression. Significance: A novel mechanism of cross-talk between ECs and VHL -deficient kidney tubules that stimulates inflammation and tumorigenesis is discovered, suggesting OSM could be a potential target for ccRCC intervention.

中文翻译：

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制瘤素 M 刺激的内皮重编程促进 VHL 缺陷肾组织的炎症和肿瘤发生

透明细胞肾细胞癌 (ccRCC) 是肾细胞癌 (RCC) 中最常见的亚型，其进展与慢性炎症有关。大约 70% 的 ccRCC 病例与 von Hippel-Lindau (VHL) 肿瘤抑制基因失活有关。然而，尚不清楚 VHL 中的突变如何编码 E3 泛素连接酶的底物识别亚基，靶向缺氧诱导因子-α (HIFα) 的 α 亚基，如何协调组织炎症和肿瘤发生。我们之前生成了在肾小管中具有条件性 Vhlh 敲除的小鼠，除了增生和转化透明细胞的出现外，还导致严重的炎症和纤维化。有趣的是，内皮细胞 (EC) 虽然不受基因操作的影响，尽管如此，基因表达发生了深刻变化，表明在促进炎症和肿瘤发生中发挥作用。制瘤素 M (OSM) 介导了 VHL 缺陷型肾小管细胞与 EC 之间的相互作用，而激活的 EC 又诱导巨噬细胞募集和极化。OSM 依赖性微环境也促进了外源性肿瘤的转移。因此，OSM 信号通过 VHL 缺陷的肾小管细胞启动炎症和致瘤微环境的重建，这在 ccRCC 的启动和进展中起着关键作用。意义：发现了 EC 和 VHL 缺陷肾小管之间刺激炎症和肿瘤发生的一种新的串扰机制，表明 OSM 可能是 ccRCC 干预的潜在目标。