Department of Pulmonology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
Aging (Albany NY). 2020 Dec 1;12(23):24394-24423. doi: 10.18632/aging.202293.
FBXW7 functions as an E3 ubiquitin ligase to mediate oncoprotein degradation via the ubiquitin-proteasome system in cancer cells, effectively inhibiting the growth and survival of tumor cells. However, little is known about the functions of FBXW7 in macrophages and the tumor immune microenvironment. In this study, we find that FBXW7 suppresses M2-like tumor-associated macrophage (TAM) polarization to limit tumor progression. We identified a significant increase in the proportion of M2-like TAMs and aggravated tumor growth in mice with myeloid FBXW7 deficiency by subcutaneous inoculation with Lewis lung carcinoma cells (LLCs). When stimulated with LLCs supernatant , FBXW7-knockout macrophages displayed increased M2 macrophage polarization and enhanced ability of supporting cancer cells growth. In mechanism, we confirmed that FBXW7 inhibited M2-like TAM polarization by mediating c-Myc degradation via the ubiquitin-proteasome system. These findings highlight the role of FBXW7 in M2-like TAM polarization and provide new insights into the potential targets for cancer immunotherapies.
FBXW7 作为一种 E3 泛素连接酶，通过细胞内的泛素-蛋白酶体系统介导癌蛋白降解，从而有效抑制肿瘤细胞的生长和存活。然而，关于 FBXW7 在巨噬细胞和肿瘤免疫微环境中的功能知之甚少。在这项研究中，我们发现 FBXW7 抑制 M2 样肿瘤相关巨噬细胞（TAM）极化，从而限制肿瘤进展。通过皮下接种 Lewis 肺癌细胞（LLCs），我们发现骨髓细胞 FBXW7 缺失会导致 M2 样 TAM 比例显著增加，肿瘤生长加剧。当用 LLC 细胞上清刺激时，FBXW7 敲除的巨噬细胞显示出 M2 巨噬细胞极化增加，并增强了支持癌细胞生长的能力。在机制上，我们证实 FBXW7 通过泛素-蛋白酶体系统介导 c-Myc 降解来抑制 M2 样 TAM 极化。这些发现强调了 FBXW7 在 M2 样 TAM 极化中的作用，并为癌症免疫治疗的潜在靶点提供了新的见解。
