{"title":"Aberrant CircTMEM45A Facilitates Inflammatory Progression of Esophageal Squamous Cell Carcinoma through m5C-Mediated NLRP3 Activation","authors":"Lingjiao Meng, Haotian Wu, Jiaxiang Wu, Ping'an Ding, Jinchen He, Tongkun Li, Xiaoman Niu, Meixiang Sang, Lihua Liu","doi":"10.1158/0008-5472.can-24-4154","DOIUrl":null,"url":null,"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.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"117 1","pages":""},"PeriodicalIF":12.5000,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/0008-5472.can-24-4154","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.