[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-329031-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-329031-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","oxidative-stress-promotes-oral-carcinogenesis-via-thbs1-mediated-m1-like-tumor-associated-macrophages-polarization","Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization","","Oxidative stress is closely linked to tumor invasion and metastasis, yet its mechanisms in the early stage of oral cancer remain unclear. Glutamine uptake regulated by ASCT2 contributes to glutathione synthesis and redox resolution. Here, ASCT2 deletion in oral epithelium induces oxidative stress and accelerates 4-NQO-driven oral carcinogenesis in transgenic knockout mice. Upregulated Thbs1 is associated with macrophage infiltration, and multiplex immunohistochemistry shows enrichment of M1-like TAMs in tumor areas. Mechanistically, ASCT2 inhibition limits glutamine uptake, increases intracellular ROS, elevates Thbs1 in oral keratinocytes, and activates p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome transfer. M1-like TAMs promote malignant progression of OSCC in vitro and in vivo, establishing an ASCT2-Thbs1-mediated M1 polarization axis and suggesting redox restoration as a prevention strategy for potentially malignant disorders.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/oxidative-stress-promotes-oral-carcinogenesis-via-thbs1-mediated-m1-like-tumor-associated-macrophages-polarization/329031/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/oxidative-stress-promotes-oral-carcinogenesis-via-thbs1-mediated-m1-like-tumor-associated-macrophages-polarization/329031.png","ImageObject",300,407,{"name":42,"@type":43},"Miles","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-04","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",5,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How does oxidative stress relate to the early initiation of oral cancer?","Question",{"text":63,"@type":64},"Oxidative stress is known to participate in tumor progression, but its precise role in the initiation stage of oral carcinogenesis is described as ambiguous. The study addresses this by focusing on how oxidative stress is triggered and how it drives early tumor development.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What is the role of ASCT2 deletion in oral tissues?",{"text":68,"@type":64},"Deleting ASCT2 in oral epithelium causes oxidative stress and promotes oral carcinogenesis in response to 4-NQO. The work links this phenotype to impaired glutamine uptake and downstream redox imbalance.",{"name":70,"@type":61,"acceptedAnswer":71},"How does Thbs1 mediate M1-like tumor-associated macrophage polarization?",{"text":72,"@type":64},"The study identifies a Thbs1 upregulation associated with macrophage infiltration and shows M1-like TAMs enriched in cancerous areas. Mechanistically, ASCT2-driven changes lead to ROS accumulation, which increases Thbs1 in oral keratinocytes and activates p38, Akt and SAPK/JNK signaling via an exosome-transferred pathway to polarize TAMs.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},329031,1790172846,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,100,105,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":97,"show_sort_weight":98,"slug":99},"Comic",60,"comic",{"id":101,"doc_module":4,"doc_module_name":25,"category_name":102,"show_sort_weight":103,"slug":104},6,"Technology",50,"technology",{"id":106,"doc_module":4,"doc_module_name":25,"category_name":107,"show_sort_weight":108,"slug":109},7,"Healthcare",40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":112,"slug":113},8,30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":55,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":111,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Redox Biology 76 (2024) 103335  \nContents lists available at ScienceDirect  \nRedox Biology  \njournal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox)  \n| Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization\u003Cbr>Wei Lia,b,1, Qingwen Zenga,b,1, Bing Wang a,b,1, Chao Lva,b, Haoan He a,b, Xi Yang c,**, Bin Cheng a,b,***, Xiaoan Taoa,b,*\u003Cbr>a Hospital ofStomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China b Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China\u003Cbr>c Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, China |  |  |\n| --- | --- | --- |\n| A R T I C L E I N F O |  | A B S T R A C T |\n| Keywords: ROSASCT2\u003Cbr>Thbs1\u003Cbr>Macrophages\u003Cbr>Oral carcinogenesis |  | Although oxidative stress is closely associated with tumor invasion and metastasis, its’ exact role and mechanism in the initial stage of oral cancer remain ambiguous. Glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) participates in glutathione synthesis to resolve oxidative stress. Currently, we firstly found that ASCT2 deletion caused oxidative stress in oral mucosa and promoted oral carcinogenesis induced by 4-Nitroquinoline-1-oxide (4-NQO) using transgenic mice of ASCT2 knockout in oral epithelium. Subsequently, we identified an upregulated gene Thbs1 linked to macrophage infiltration by mRNA sequencing and immunohistochemistry. Importantly, multiplex immunohistochemistry showed M1-like tumor-associated macrophages (TAMs) were enriched in cancerous area. Mechanically, targeted ASCT2 effectively curbed glutamine uptake and caused intracellular reactive oxygen species (ROS) accumulation, which upregulated Thbs1 in oral keratinocytesand then activated p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome-transferred pathway. Moreover, we demonstrated M1-like TAMs promoted malignant progression of oral squamous cell carcinoma (OSCC) both in vitro and in vivo by a DOK transformed cell line induced by 4-NQO. All these results establish that oxidative stress triggered by ASCT2 deletion promotes oral carcinogenesis through Thbs1-mediated M1 polarization, and indicate that restore redox homeostasis is a new approach to prevent malignant progression of oral potentially malignant disorders. |\n\n1. Introduction  \nOxidative stress is defined as deregulation of reactive oxygen species (ROS) production and ROS limitation, characterized by unspecific oxidation of biomolecules and alteration of normal physiological function. Aberrant redox homeostasis plays important roles in regulating  \ndiverse aspects of cell behavior (e.g., proliferation, differentiation, migration and angiogenesis) [1]. It has been proven that oxidative stress is closely associated with tumor progression. On the one hand, oxidative stress triggers tumor development by causing DNA damage and genomic instability [2,3]; on the other hand, the rapid growth of tumor enhances ROS production [4,5]. However, it remains obscure on the role and  \nAbbreviations: ASCT2, alanine-serine-cysteine transporter 2; SLC, solute carrier; 4-NQO, 4-Nitroquinoline-1-oxide; TAMs, tumor-associated macrophages; ROS, reactive oxygen species; OSCC, oral squamous cell carcinoma; Gln, glutamine; TCA, tricarboxylic acid; GSH, glutathione; OLK, oral leukoplakia; OPMDs, oral potentially malignant disorders; DOK, dysplastic oral keratinocytes; FBS, fetal bovine serum; HE, hematoxylin-eosin staining; IHC, immunohistochemistry staining; IF, immunofluorescence staining; mIHC, multiplex immunohistochemistry staining; DHE, dihydroethidium; FPKMs, fragments per kb of transcript per million reads; DEGs, differentially expressed genes; GO, gene ontology enrichment; KEGG, kyoto encyclopedia of genes and genomes; HNSCC, head and neck squamous cell carcinoma; qPCR, quantitative real-time PCR","cbCaipd0NzWNMxyJ","https://ap.wps.com/l/cbCaipd0NzWNMxyJ","pdf",25950296,18,"English","# Introduction\n## Oxidative stress and redox homeostasis in tumor initiation\n## Glutamine metabolism, GSH synthesis, and ASCT2 function\n## Macrophage polarization and Thbs1-related mechanisms","[{\"question\":\"How does oxidative stress relate to the early initiation of oral cancer?\",\"answer\":\"Oxidative stress is known to participate in tumor progression, but its precise role in the initiation stage of oral carcinogenesis is described as ambiguous. The study addresses this by focusing on how oxidative stress is triggered and how it drives early tumor development.\"},{\"question\":\"What is the role of ASCT2 deletion in oral tissues?\",\"answer\":\"Deleting ASCT2 in oral epithelium causes oxidative stress and promotes oral carcinogenesis in response to 4-NQO. The work links this phenotype to impaired glutamine uptake and downstream redox imbalance.\"},{\"question\":\"How does Thbs1 mediate M1-like tumor-associated macrophage polarization?\",\"answer\":\"The study identifies a Thbs1 upregulation associated with macrophage infiltration and shows M1-like TAMs enriched in cancerous areas. Mechanistically, ASCT2-driven changes lead to ROS accumulation, which increases Thbs1 in oral keratinocytes and activates p38, Akt and SAPK/JNK signaling via an exosome-transferred pathway to polarize TAMs.\"}]","Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization | PDF",1789982132,45]