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CD73 通过调节胃癌中的 RICS/RhoA 信号和 EMT 促进肿瘤转移。

CD73 promotes tumor metastasis by modulating RICS/RhoA signaling and EMT in gastric cancer.

机构信息

Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

出版信息

Cell Death Dis. 2020 Mar 23;11(3):202. doi: 10.1038/s41419-020-2403-6.

DOI:10.1038/s41419-020-2403-6
PMID:32205841
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7089986/
Abstract

Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5'-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

摘要

肿瘤微环境在塑造癌症异质性方面起着至关重要的作用，CD73（外核苷酸酶；NT5E）是一种新兴的免疫检查点，通过将免疫刺激性 ATP 转化为免疫抑制性腺苷来调节癌症进展。然而，CD73 的调控方式以及它在癌症进展中的作用在很大程度上是未知的。在这里，我们表明 CD73 过表达与胃癌的预后不良相关。CD73 通过微环境转换中的腺苷能信号将上皮-间充质转化表型与胃癌转移过程中的表型联系起来。对转录组数据的进一步通路和基因集富集分析显示，CD73 通过其在腺苷能途径中的细胞外功能，在 RICS/RhoA 信号中具有调节作用，随后抑制 LIMK/丝切蛋白的磷酸化并促进 β-连环蛋白的激活。发现 CD73 腺苷能信号的药理学抑制可诱导 RICS 功能障碍。传播和血液转移模型表明，在胃癌中靶向 CD73 可以抑制实验性转移。总之，它证实了 CD73 是治疗胃癌转移的靶点，并验证了 RICS 作为一种将 CD73/腺苷能信号转换与 RhoA/LIMK/丝切蛋白通路联系起来的细胞内功能分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/673a0c294676/41419_2020_2403_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/914737642d8e/41419_2020_2403_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/f90c020a3940/41419_2020_2403_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/1f8d7823eb06/41419_2020_2403_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/a60817dafe41/41419_2020_2403_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/55dd946e2bab/41419_2020_2403_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/35b68607474a/41419_2020_2403_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/673a0c294676/41419_2020_2403_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/914737642d8e/41419_2020_2403_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/f90c020a3940/41419_2020_2403_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/1f8d7823eb06/41419_2020_2403_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/a60817dafe41/41419_2020_2403_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/55dd946e2bab/41419_2020_2403_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/35b68607474a/41419_2020_2403_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f5c/7089986/673a0c294676/41419_2020_2403_Fig7_HTML.jpg

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