ADARp110 promotes hepatocellular carcinoma progression via stabilization of CD24 mRNA

IF 9.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-01-14 DOI:10.1073/pnas.2409724122

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

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引用次数: 0

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 Adarp110 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 GZMB + CD8 + 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.

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ADARp110通过稳定CD24 mRNA促进肝细胞癌进展

ADAR在肝细胞癌（HCC）中高表达并与预后不良相关，但其组成异构体ADARp110在肿瘤发生中的作用尚不清楚。我们通过临床样本、肝细胞特异性ADARp110敲入小鼠模型和工程细胞系研究了ADARp110在HCC中的作用及其潜在机制。ADARp110在人和小鼠HCC中均过表达并与低生存率相关。它通过抑制总免疫细胞，特别是细胞毒性GZMB + CD8 + T细胞的浸润，同时增加Treg细胞、MDSCs和耗尽CD8 + T细胞的比例，产生免疫抑制微环境。从机制上讲，ADARp110与SNRPD3和RNPS1相互作用，通过抑制stau1介导的mRNA衰变来稳定CD24 mRNA。CD24保护HCC细胞免受两种不可缺少的机制：巨噬细胞吞噬和氧化应激。CD24基因敲除或单克隆抗体治疗可抑制adarp110过表达的肿瘤生长。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的一个有希望的治疗靶点。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.