Aberrant CircTMEM45A Facilitates Inflammatory Progression of Esophageal Squamous Cell Carcinoma through m5C-Mediated NLRP3 Activation

IF 12.5 1区 医学 Q1 ONCOLOGY
Lingjiao Meng, Haotian Wu, Jiaxiang Wu, Ping'an Ding, Jinchen He, Tongkun Li, Xiaoman Niu, Meixiang Sang, Lihua Liu
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Abstract

The lack of diagnostic and therapeutic targets precludes effective treatment of esophageal cancer, rooted in the limited mechanistic understanding of cancer initiation and progression. Non-mutational epigenetic reprogramming, including altered 5-methylcytosine (m5C) modification and circular RNA (circRNA) expression, can drive tumorigenesis and impact cancer biology. Herein, we identified upregulation of the circRNA hsa_circ_0066658 (termed as circTMEM45A) in esophageal squamous cell carcinoma (ESCC) tissues, which was correlated with advanced clinical stages and poor survival. Functionally, elevated circTMEM45A facilitated ESCC malignant progression both in vitro and in vivo. Mechanistically, circTMEM45A interacted with the methyltransferase NSUN2 and m5C readers ALYREF and YBX1, promoting the nuclear export and stability of NLRP3 mRNA to activate the NLRP3/caspase 1/IL-1β inflammatory pathway. Additionally, circTMEM45A stabilized IL1B mRNA by binding to U2AF2 and stabilized IL1R1 mRNA by serving as a protein scaffold to enhance the IGF2BP2/HUR interaction, further activating the IL-1β/IL1R1 pro-inflammatory cascade in the tumor microenvironment. These findings reveal crosstalk between circRNA and m5C modification that drives inflammatory progression, highlighting circTMEM45A as a potential diagnostic and therapeutic target in ESCC.
异常CircTMEM45A通过m5c介导的NLRP3激活促进食管鳞状细胞癌的炎症进展
缺乏诊断和治疗靶点阻碍了食管癌的有效治疗,其根源在于对癌症发生和进展的机制理解有限。非突变表观遗传重编程,包括改变5-甲基胞嘧啶(m5C)修饰和环状RNA (circRNA)表达,可以驱动肿瘤发生并影响癌症生物学。本文中,我们发现circRNA hsa_circ_0066658(称为circTMEM45A)在食管鳞状细胞癌(ESCC)组织中表达上调,这与晚期临床分期和较差的生存率相关。在功能上,circTMEM45A的升高促进了体外和体内ESCC的恶性进展。机制上,circTMEM45A与甲基转移酶NSUN2和m5C读取器ALYREF和YBX1相互作用,促进NLRP3 mRNA的核输出和稳定性,激活NLRP3/caspase 1/IL-1β炎症通路。此外,circTMEM45A通过与U2AF2结合来稳定IL1B mRNA,并通过作为蛋白支架来增强IGF2BP2/HUR相互作用来稳定IL1R1 mRNA,进一步激活肿瘤微环境中IL-1β/IL1R1促炎症级联反应。这些发现揭示了circRNA和m5C修饰之间的串扰,驱动炎症进展,突出了circTMEM45A作为ESCC的潜在诊断和治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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