ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-09-06 DOI:10.1002/mc.23818
Dongsheng He, Chao Niu, Rilan Bai, Naifei Chen, Jiuwei Cui
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Abstract

The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.

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ADAR1 通过 FAK/AKT 通路促进结直肠癌的侵袭和迁移并抑制铁凋亡
人们对作用于RNA1的腺苷脱氨酶(ADAR1)在结直肠癌(CRC)中的作用知之甚少。本研究探讨了ADAR1及其同工型的作用和潜在分子机制,探索了ADAR1表达与免疫微环境和抗癌药物敏感性之间的相关性,并研究了利用ADAR1表达和临床参数判断CRC患者预后的潜在协同作用。CRC样本显示ADAR1明显上调,ADAR1高表达与预后不良相关。沉默ADAR1可抑制CRC细胞的增殖、侵袭和迁移,并通过抑制FAK/AKT活化诱导铁变态反应。ADAR1-p110和ADAR1-p150都被证明能调节FAK/AKT通路,其中ADAR1-p110的作用尤为重要。在评估 CRC 患者的预后时,将 ADAR1 表达与临床参数相结合会产生很大的协同效应。沉默 ADAR1 能显著抑制 CRC 的体内肿瘤发生。此外,ADAR1的表达与肿瘤突变负荷(TMB)和微卫星状态呈正相关(p
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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