Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In this study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, and inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2-binding and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.

中文翻译：

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USP17通过调节TRAF2 / TRAF3复合物的形成介导肺癌细胞中巨噬细胞促进的炎症和干性。

由于压力和疾病引起的巨噬细胞在肺中的积累和炎症是肺癌发展的原因。然而，对巨噬细胞和癌细胞之间相互作用的分子机制的了解甚少，而这种分子机制导致了癌症的炎症和干性。在这项研究中，我们调查了泛素特异性肽酶17（USP17）在肺癌中的表达以及USP17升高在巨噬细胞和肺癌细胞之间相互作用中的作用。肺癌中USP17的表达与不良预后，巨噬细胞和炎症标志物的表达有关。巨噬细胞促进了USP17在癌细胞中的表达。在USP17中鉴定了TNFR相关因子（TRAF）2结合和TRAF3结合基序，通过它与TRAF2 / TRAF3复合物相互作用并破坏了它。这样可以稳定其客户蛋白质，增强癌细胞的炎症和干性，并促进巨噬细胞募集。在不同的动物研究中，巨噬细胞与癌细胞的共同注射促进了USP17在肿瘤和肿瘤生长中的表达。相反，氯膦酸盐脂质体耗尽宿主动物中的巨噬细胞会降低USP17表达和肿瘤生长。此外，USP17在癌细胞中的过表达促进了肿瘤的生长以及肿瘤中与炎症相关和与干性相关的基因表达。这些结果表明USP17驱动巨噬细胞和癌细胞之间的正反馈相互作用，以增强癌细胞的炎症和干性，并促进肺癌的生长。巨噬细胞与癌细胞的共同注射促进了USP17在肿瘤和肿瘤生长中的表达。相反，氯膦酸盐脂质体耗尽宿主动物中的巨噬细胞会降低USP17表达和肿瘤生长。此外，USP17在癌细胞中的过表达促进了肿瘤的生长以及肿瘤中与炎症相关和与干性相关的基因表达。这些结果表明USP17驱动巨噬细胞和癌细胞之间的正反馈相互作用，以增强癌细胞的炎症和干性，并促进肺癌的生长。巨噬细胞与癌细胞的共同注射促进了USP17在肿瘤和肿瘤生长中的表达。相反，氯膦酸盐脂质体耗尽宿主动物中的巨噬细胞会降低USP17表达和肿瘤生长。此外，USP17在癌细胞中的过表达促进了肿瘤的生长以及肿瘤中与炎症相关和与干性相关的基因表达。这些结果表明USP17驱动巨噬细胞和癌细胞之间的正反馈相互作用，以增强癌细胞的炎症和干性，并促进肺癌的生长。USP17在癌细胞中的过表达促进了肿瘤的生长以及肿瘤中与炎症相关和与干性相关的基因表达。这些结果表明USP17驱动巨噬细胞和癌细胞之间的正反馈相互作用，以增强癌细胞的炎症和干性，并促进肺癌的生长。USP17在癌细胞中的过表达促进了肿瘤的生长以及肿瘤中与炎症相关和与干性相关的基因表达。这些结果表明USP17驱动巨噬细胞和癌细胞之间的正反馈相互作用，以增强癌细胞的炎症和干性，并促进肺癌的生长。