A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression.
A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression.
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DOI：
10.1038/s41420-022-00968-9
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发表时间：
2022-04-12
影响因子：
7
通讯作者：
Yin, Yongmei
中科院分区：
文献类型：
--
作者：
Yan, Xueqi;He, Yaozhou;Yang, Shikun;Zeng, Tianyu;Hua, Yijia;Bao, Shengnan;Yang, Fan;Duan, Ningjun;Sun, Chunxiao;Liang, Yan;Fu, Ziyi;Huang, Xiang;Li, Wei;Yin, Yongmei
作为DNA跨损伤合成（TLS）途径的关键调节因子，RAD 18是易于出错的，并有助于DNA突变的积累。我们以前的研究表明，它在多种肿瘤的进展中起着至关重要的作用。然而，RAD 18影响三阴性乳腺癌（TNBC）的机制，特别是肿瘤细胞与肿瘤微环境之间的相互作用，仍然是难以捉摸的。在这项研究中，我们发现，RAD 18的表达在高T期TNBC患者中明显较高，并与预后呈负相关。RAD 18的高表达通过支持TNBC增殖的Hippo/雅普途径促进高度干细胞表型。此外，细胞因子副产物TGF-β激活巨噬细胞以具有M2样肿瘤相关巨噬细胞（TAM）表型。反过来，来自TAM的TGF-β激活TNBC中的RAD 18以增强肿瘤的干性，形成正反馈回路。雅普或TGF-β的抑制打破了这一循环，并抑制了癌的干性和增殖。在裸鼠中，RAD 18促进皮下移植肿瘤的生长和M2型TAM的募集。总的来说，RAD 18-YAP-TGF-β环对于TNBC促进干性表型是必需的，并且可以是TNBC的潜在治疗靶标。
As a key regulator of the DNA translesion synthesis (TLS) pathway, RAD18 is error-prone and contributes to the accumulation of DNA mutations. Our previous study showed that it plays an essential role in the progression of multiple tumors. However, the mechanism through which RAD18 influences triple-negative breast cancer (TNBC), especially the interaction between tumor cells and the tumor microenvironment, remains elusive. In this study, we showed that RAD18 expression is markedly higher in patients with high T stage TNBC and inversely correlated with prognosis. High expression of RAD18 facilitated a highly stem-cell phenotype through the Hippo/YAP pathway, which supports the proliferation of TNBC. In addition, the cytokine byproduct TGF-β activates macrophages to have an M2-like tumor-associated macrophage (TAM) phenotype. Reciprocally, TGF-β from TAMs activated RAD18 in TNBC to enhance tumor stemness, forming a positive feedback loop. Inhibition of YAP or TGF-β breaks this loop and suppresses cancer stemness and proliferation In nude mice, RAD18 promoted subcutaneous transplanted tumor growth and M2-type TAM recruitment. Collectively, the RAD18-YAP-TGF-β loop is essential for the promotion of the stemness phenotype by TNBC and could be a potential therapeutic target for TNBC.
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影响因子：
10.5
作者：
Guo X;Zhao Y;Yan H;Yang Y;Shen S;Dai X;Ji X;Ji F;Gong XG;Li L;Bai X;Feng XH;Liang T;Ji J;Chen L;Wang H;Zhao B
通讯作者：
Zhao B
DOI：
10.1007/s00432-007-0272-3
发表时间：
2008-02-01
影响因子：
3.6
作者：
Kanzaki, Hirotaka;Ouchida, Mamoru;Shimizu, Kenji
通讯作者：
Shimizu, Kenji
影响因子：
16.6
作者：
Lee, Joanna Y.;Chang, Jessica K.;Chaudhuri, Ovijit
通讯作者：
Chaudhuri, Ovijit
DOI：
10.1073/pnas.0605146103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Bachl, Juergen;Ertongur, Isin;Jungnickel, Berit
通讯作者：
Jungnickel, Berit
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia