[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-342558-105":3,"detail-sidebar-cat-0-en-105":80,"doc-detail-342558-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":73,"head_meta":75,"extra_data":77,"updated_unix":79},105,"en","tight-junction-protein-cingulin-variant-is-associated-with-cancer-susceptibility-by-overexpressed-iqgap1-and-rac1-dependent-epithelial-mesenchymal-transition","Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition","","Cingulin (CGN) is a tight-junction cytoskeletal adaptor implicated in cancer biology. This study examines whether CGN mutation increases cancer susceptibility by integrating tumor-targeted and germline whole-genome sequencing from a high-cancer-density family, followed by validation in a 222-patient cohort. CGN c.3560C>T accelerates tumor progression, reduces oxaliplatin sensitivity, drives epithelial-mesenchymal transition via IQGAP1 overexpression, and activates Rac1. Rac1 inhibition using NSC23766 attenuates EMT and tumor growth in CGN c.3560C>T models. Targeting activated Rac1 is proposed as a strategy for cancers carrying this variant.",{"@graph":14,"@context":72},[15,34,55],{"@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/tight-junction-protein-cingulin-variant-is-associated-with-cancer-susceptibility-by-overexpressed-iqgap1-and-rac1-dependent-epithelial-mesenchymal-transition/342558/",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/tight-junction-protein-cingulin-variant-is-associated-with-cancer-susceptibility-by-overexpressed-iqgap1-and-rac1-dependent-epithelial-mesenchymal-transition/342558.png","ImageObject",300,407,{"name":42,"@type":43},"Anda","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":52,"interactionType":53,"userInteractionCount":22},"InteractionCounter",{"@type":54},"ViewAction",{"@type":56,"mainEntity":57},"FAQPage",[58,64,68],{"name":59,"@type":60,"acceptedAnswer":61},"What is the main finding about the CGN c.3560C>T variant?","Question",{"text":62,"@type":63},"CGN c.3560C>T enhances tumor progression, increases EMT features, and is linked to reduced oxaliplatin sensitivity compared with the CGN wild type.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"How does the variant promote EMT mechanistically?",{"text":67,"@type":63},"The variant induces overexpression of IQGAP1, which is associated with activation of Rac1; activated Rac1 supports EMT progression in cancer cells carrying CGN c.3560C>T.",{"name":69,"@type":60,"acceptedAnswer":70},"Why does inhibiting Rac1 matter for cancers with this CGN variant?",{"text":71,"@type":63},"Downregulating IQGAP1 suppresses Rac1 activation, and Rac1-GEF inhibition with NSC23766 mitigates the EMT program and attenuates tumor growth in xenografts harboring c.3560C>T, while WT tumors show no sensitivity.","https://schema.org",{"og:url":32,"og:type":74,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":76,"canonical":32},"index,follow",{"doc_id":78,"site_id":7},342558,1790181904,{"code":4,"msg":81,"data":82},"success",[83,87,91,95,100,105,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":84,"show_sort_weight":85,"slug":86},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":88,"show_sort_weight":89,"slug":90},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":92,"show_sort_weight":93,"slug":94},"Exam",70,"exam",{"id":96,"doc_module":4,"doc_module_name":25,"category_name":97,"show_sort_weight":98,"slug":99},5,"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":96,"slug":129},19,"General","general",{"code":4,"msg":81,"data":131},{"doc_id":78,"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":22,"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},962075006959,"https://ap-avatar.wpscdn.com/avatar/e0002397efbe92a78e?_k=1776741047341049297","Huang et al. J Exp Clin Cancer Res (2024) 43:65 [https://doi.org/10.1186/s13046-024-02987-z](https://doi.org/10.1186/s13046-024-02987-z)  \nJournal of Experimental & Clinical Cancer Research  \n RESEARCH Open Access  \nTight junction protein cingulin variant  \nis associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition  \nYi‑Ting Huang 1,2†, Ya‑Ting Hsu3,4†, Pei‑Ying Wu5, Yu‑Min Yeh6, Peng‑Chan Lin6, Keng‑Fu Hsu5 and Meng‑Ru Shen 1,3,5*  \nAbstract  \nBackground Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investi‑ gates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analyses and proposes a potential targeted therapeutic approach.  \nMethods In a high‑cancer‑density family without known pathogenic variants, we performed tumor‑targeted and germline whole‑genome sequencing to identify novel cancer‑associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c. 3560C >T was identified as a potential cancer‑risk allele.  \nBoth wild‑type (WT) (c. 3560C >C) and variant (c. 3560C >T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluo‑ rescence analysis, migration and invasion assays, two‑dimensional gel electrophoresis with mass spectrometry, immu‑ noprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c. 3560C >T. Results In cancer cell lines and orthotopic animal models, CGN c. 3560C >T enhanced tumor progression  \nwith reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithe‑  \nlial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial‑ mesenchymal transition (EMT) . Proteomic analysis was conducted to investigate the elements driving EMT in CGNc. 3560C >T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1 . IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harbor‑ ing CGN c. 3560C >T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treat‑ ment with NSC23766, a selective inhibitor for Rac1‑GEF interaction, resulted in the inactivation of Rac1 . This interven‑ tion mitigated the EMT program in cancer cells carrying CGN c. 3560C >T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c. 3560C >T.  \n†Yi‑Ting Huang andYa‑Ting Hsu have contributed equally to this work.  \n*Correspondence: Meng‑Ru Shen[mrshen@mail.ncku.edu.tw](mrshen@mail.ncku.edu.tw)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To v","cbCainj0N6DA73p9","https://ap.wps.com/l/cbCainj0N6DA73p9","pdf",3140214,15,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Keywords\n# Background","[{\"question\":\"What is the main finding about the CGN c.3560C\\u003eT variant?\",\"answer\":\"CGN c.3560C\\u003eT enhances tumor progression, increases EMT features, and is linked to reduced oxaliplatin sensitivity compared with the CGN wild type.\"},{\"question\":\"How does the variant promote EMT mechanistically?\",\"answer\":\"The variant induces overexpression of IQGAP1, which is associated with activation of Rac1; activated Rac1 supports EMT progression in cancer cells carrying CGN c.3560C\\u003eT.\"},{\"question\":\"Why does inhibiting Rac1 matter for cancers with this CGN variant?\",\"answer\":\"Downregulating IQGAP1 suppresses Rac1 activation, and Rac1-GEF inhibition with NSC23766 mitigates the EMT program and attenuates tumor growth in xenografts harboring c.3560C\\u003eT, while WT tumors show no sensitivity.\"}]","Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition | PDF",1790047128,38]