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ADARp110通过稳定CD24信使核糖核酸促进肝细胞癌进展。

ADARp110 promotes hepatocellular carcinoma progression via stabilization of CD24 mRNA.

作者信息

Sun Liangzhan, Hu Pengchao, Yang Hui, Ren Jun, Hu Rong, Wu Shasha, Wang Yanchen, Du Yuyang, Zheng Jingyi, Wang Fenfen, Gao Han, Yan Jingsong, Yuan Yun-Fei, Guan Xin-Yuan, Xiao Jia, Li Yan

机构信息

Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.

Department of Clinical Oncology, The University of Hong Kong, Hong Kong 999077, China.

出版信息

Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2409724122. doi: 10.1073/pnas.2409724122. Epub 2025 Jan 14.

DOI:10.1073/pnas.2409724122
PMID:39808660
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11761664/
Abstract

ADAR is highly expressed and correlated with poor prognosis in hepatocellular carcinoma (HCC), yet the role of its constitutive isoform ADARp110 in tumorigenesis remains elusive. We investigated the role of ADARp110 in HCC and underlying mechanisms using clinical samples, a hepatocyte-specific knock-in mouse model, and engineered cell lines. ADARp110 is overexpressed and associated with poor survival in both human and mouse HCC. It creates an immunosuppressive microenvironment by inhibiting total immune cells, particularly cytotoxic GZMBCD8 T cells infiltration, while augmenting Treg cells, MDSCs, and exhausted CD8 T cells ratios. Mechanistically, ADARp110 interacts with SNRPD3 and RNPS1 to stabilize CD24 mRNA by inhibiting STAU1-mediated mRNA decay. CD24 protects HCC cells from two indispensable mechanisms: macrophage phagocytosis and oxidative stress. Genetic knockdown or monoclonal antibody treatment of CD24 inhibits ADARp110-overexpressing tumor growth. Our findings unveil different mechanisms for ADARp110 modulation of tumor immune microenvironment and identify CD24 as a promising therapeutic target for HCCs.

摘要

腺苷脱氨酶作用于RNA（ADAR）在肝细胞癌（HCC）中高表达且与预后不良相关，但其组成型异构体ADARp110在肿瘤发生中的作用仍不清楚。我们使用临床样本、肝细胞特异性敲入小鼠模型和工程细胞系研究了ADARp110在HCC中的作用及潜在机制。ADARp110在人类和小鼠HCC中均过表达且与生存率低相关。它通过抑制总免疫细胞，特别是细胞毒性颗粒酶B（GZMB）+ CD8 + T细胞浸润，同时增加调节性T细胞（Treg）、骨髓来源的抑制细胞（MDSC）和耗竭的CD8 + T细胞比例，营造了一种免疫抑制微环境。从机制上讲，ADARp110与小核核糖核蛋白结构域蛋白3（SNRPD3）和富含精氨酸及脯氨酸的剪接因子1（RNPS1）相互作用，通过抑制Staufen 1（STAU1）介导的mRNA衰变来稳定CD24 mRNA。CD24通过两种不可或缺的机制保护HCC细胞：巨噬细胞吞噬作用和氧化应激。对CD24进行基因敲低或单克隆抗体处理可抑制ADARp110过表达肿瘤的生长。我们的研究结果揭示了ADARp110调节肿瘤免疫微环境的不同机制，并确定CD24是HCC的一个有前景的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/6aea4561d923/pnas.2409724122fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/b97ba9a2ffad/pnas.2409724122fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/7d4dd9592ef7/pnas.2409724122fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/d14005a5ac17/pnas.2409724122fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/90d4049aaa87/pnas.2409724122fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/272604446087/pnas.2409724122fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/b2b655651942/pnas.2409724122fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/6aea4561d923/pnas.2409724122fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/b97ba9a2ffad/pnas.2409724122fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/7d4dd9592ef7/pnas.2409724122fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/d14005a5ac17/pnas.2409724122fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/90d4049aaa87/pnas.2409724122fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/272604446087/pnas.2409724122fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/b2b655651942/pnas.2409724122fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f22c/11761664/6aea4561d923/pnas.2409724122fig07.jpg

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本文引用的文献

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Evolving therapeutic landscape of advanced hepatocellular carcinoma.
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ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis.ADAR1 掩盖了 ZBP1 驱动的坏死性凋亡的癌症免疫治疗潜力。
Nature. 2022 Jun;606(7914):594-602. doi: 10.1038/s41586-022-04753-7. Epub 2022 May 25.
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ADAR1 and its implications in cancer development and treatment.ADAR1 及其在癌症发生和治疗中的意义。
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