Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry.
Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry.
复制标题
肿瘤相关巨噬细胞衍生的外泌体传递miR - 193a - 5p通过依赖TIMP2的血管生成拟态促进肾细胞癌的进展。
DOI：
10.1038/s41419-022-04814-9
复制
发表时间：
2022-04-20
影响因子：
9
通讯作者：
You, Bosen
中科院分区：
文献类型：
--
作者：
Liu, Qing;Zhao, Enyang;Geng, Bo;Gao, Shan;Yu, Hongyang;He, Xinyang;Li, Xuedong;Dong, Guanglu;You, Bosen
先前的研究已经探讨了肿瘤相关巨噬细胞（TAMs）是否发挥致瘤和免疫抑制作用以促进癌症发展，但TAMs在调节透明细胞肾细胞癌（ccRCC）细胞血管生成拟态（VM）中的作用尚未完全阐明。我们对ccRCC人类标本中的肿瘤相关巨噬细胞生物标志物CD68/CD163进行免疫染色，并对PAS/CD31进行双重染色，发现较高的TAM浸润与VM形成呈正相关。然后我们证明，TAM衍生的外泌体通过转运miR - 193a - 5p下调肾癌细胞中TIMP2的表达，从而促进VM和侵袭。机制分析表明，巨噬细胞中HIF - 1α的上调可转录性增加miR - 193a - 5p的表达。外泌体转运的miR - 193a - 5p随后靶向TIMP2 mRNA的3′非翻译区（UTR）以抑制其翻译。一项在小鼠体内进行的ccRCC原位异种移植模型的临床前研究证实，TAM衍生的外泌体增强VM并使肿瘤进展，这证实了我们的体外数据。抑制TAM衍生的外泌体miR - 193a - 5p成功地抑制了肿瘤进展和转移。总体而言，来自TAM衍生外泌体的miR - 193a - 5p下调TIMP2基因以促进肾细胞癌的发展，这为制定肾细胞癌的治疗策略提供了新的视角。
Previous studies have investigated whether tumor-associated macrophages (TAMs) play tumorigenic and immunosuppressive roles to encourage cancer development, but the role of TAMs in regulating vasculogenic mimicry (VM) in clear-cell renal cell carcinoma (ccRCC) cells has not been completely clarified. We conducted immunostaining of the tumor-associated macrophage biomarkers CD68/CD163 and double staining for PAS/CD31 in ccRCC human specimens to find that higher TAM infiltration was positively correlated with VM formation. Then we demonstrated that TAM-derived exosomes downregulate TIMP2 expression in RCC cells to promote VM and invasion by shuttling miR-193a-5p. Mechanistic analysis indicated that HIF-1α upregulation in macrophages could transcriptionally increase miR-193a-5p expression. Exosome-shuttled miR-193a-5p then targeted the 3′ untranslated region (UTR) of TIMP2 mRNA to suppress its translation. A preclinical study using an in vivo orthotopic xenograft model of ccRCC in mice substantiated that TAM-derived exosomes enhance VM and enable tumor progression, which confirmed our in vitro data. Suppressing TAM-derived exosomal miR-193a-5p successfully inhibited tumor progression and metastasis. Overall, miR-193a-5p from TAM-derived exosomes downregulates the TIMP2 gene to facilitate the development of RCC, which provides a novel perspective for developing therapeutic strategies for RCC.
登录
查看更多内容
影响因子：
8
作者：
Chen XW;Yu TJ;Zhang J;Li Y;Chen HL;Yang GF;Yu W;Liu YZ;Liu XX;Duan CF;Tang HL;Qiu M;Wang CL;Zheng H;Yue J;Guo AM;Yang J
通讯作者：
Yang J
影响因子：
16.6
作者：
Velez DO;Tsui B;Goshia T;Chute CL;Han A;Carter H;Fraley SI
通讯作者：
Fraley SI
影响因子：
7.3
作者：
Adamo, Annalisa;Brandi, Jessica;Krampera, Mauro
通讯作者：
Krampera, Mauro
靶向肿瘤-巨噬细胞相互作用中的正调节环可损害透明细胞肾细胞癌的进展。
影响因子：
12.4
作者：
Wang, Chao;Wang, Yuning;Cui, Xingang
通讯作者：
Cui, Xingang
影响因子：
37.3
作者：
Delgado-Bellido D;Serrano-Saenz S;Fernández-Cortés M;Oliver FJ
通讯作者：
Oliver FJ