Ronghao Zou, Juan Lu, Xiaoyue Bai, Yuyao Yang, Shouyue Zhang, Shuai Wu, Zhixin Tang, Kang Li, Xiaohui Hua
{"title":"暴露于苯并[a]芘及其代谢物 BPDE 的膀胱上皮细胞中,LOXL1 蛋白的表观遗传修饰下调介导了 EMT。","authors":"Ronghao Zou, Juan Lu, Xiaoyue Bai, Yuyao Yang, Shouyue Zhang, Shuai Wu, Zhixin Tang, Kang Li, Xiaohui Hua","doi":"10.1016/j.intimp.2024.113232","DOIUrl":null,"url":null,"abstract":"<p><p>Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"142 Pt B","pages":"113232"},"PeriodicalIF":4.8000,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The epigenetic-modified downregulation of LOXL1 protein mediates EMT in bladder epithelial cells exposed to benzo[a]pyrene and its metabolite BPDE.\",\"authors\":\"Ronghao Zou, Juan Lu, Xiaoyue Bai, Yuyao Yang, Shouyue Zhang, Shuai Wu, Zhixin Tang, Kang Li, Xiaohui Hua\",\"doi\":\"10.1016/j.intimp.2024.113232\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer.</p>\",\"PeriodicalId\":13859,\"journal\":{\"name\":\"International immunopharmacology\",\"volume\":\"142 Pt B\",\"pages\":\"113232\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-12-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International immunopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.intimp.2024.113232\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.intimp.2024.113232","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/27 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
The epigenetic-modified downregulation of LOXL1 protein mediates EMT in bladder epithelial cells exposed to benzo[a]pyrene and its metabolite BPDE.
Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.