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肿瘤相关巨噬细胞衍生的外泌体传递 miR-193a-5p 通过 TIMP2 依赖性血管生成拟态促进肾细胞癌的进展。

Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry.

机构信息

Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.

Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.

出版信息

Cell Death Dis. 2022 Apr 20;13(4):382. doi: 10.1038/s41419-022-04814-9.

DOI:10.1038/s41419-022-04814-9
PMID:35443741
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9021253/
Abstract

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.

摘要

先前的研究已经探讨了肿瘤相关巨噬细胞（TAMs）是否发挥肿瘤发生和免疫抑制作用来促进癌症发展，但 TAMs 在调节肾透明细胞癌（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标志物 CD68/CD163 进行免疫染色，并对 PAS/CD31 进行双重染色，发现 TAM 浸润程度越高，VM 形成呈正相关。然后，我们证明 TAM 衍生的外泌体下调 RCC 细胞中的 TIMP2 表达，通过转移 miR-193a-5p 来促进 VM 和侵袭。机制分析表明，巨噬细胞中 HIF-1α 的上调可以转录性增加 miR-193a-5p 的表达。外泌体转移的 miR-193a-5p 随后靶向 TIMP2 mRNA 的 3'非翻译区（UTR），抑制其翻译。在小鼠体内 ccRCC 原位异种移植模型中的临床前研究证实，TAM 衍生的外泌体增强了 VM 并促进了肿瘤进展，这证实了我们的体外数据。抑制 TAM 衍生的外泌体 miR-193a-5p 成功抑制了肿瘤的进展和转移。总的来说，TAM 衍生的外泌体中的 miR-193a-5p 下调 TIMP2 基因，促进了 RCC 的发展，为开发 RCC 的治疗策略提供了新的视角。

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