Chemokine CCL5 is transcriptionally suppressed by ΔNp63 and facilitates progression of head and neck squamous cell carcinoma

Chemokine CCL5 is transcriptionally suppressed by ΔNp63 and facilitates progression of head and neck squamous cell carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Chemokine CCL5 is transcriptionally suppressed by ΔNp63 and facilitates progression of head and neck squamous cell carcinoma Chenghua Li, Xiushuang Luo, Jinqi Ji, Ke Hu, Yin Xie, Shijie Fan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8549358/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Head and neck squamous cell carcinoma (HNSCC), the eighth most common cancer globally, is characterized by poor prognosis and high metastatic potential. Although transcription factor ΔNp63 is known to promote HNSCC proliferation while suppressing epithelial-mesenchymal transition (EMT) and migration, its underlying molecular mechanisms remain unclear. Here, we demonstrate that ΔNp63 acts as a transcriptional repressor by directly binding to the promoter of CCL5 gene, which encodes a chemokine. We find that CCL5 is upregulated in HNSCC and drives cell proliferation and migration in vitro and in vivo. Further experiments reveal that CCL5 mediates ΔNp63's inhibitory effects on EMT, migration, and metastasis. Mechanistically, CCL5 triggers intracellular ERK signaling axis to promote EMT of HNSCC cells, leading to elevated in vitro migration and in vivo metastasis; on the other hand, CCL5 activates mTOR pathway, which may contribute to maintaining cell proliferation upon repression of ΔNp63. Additionally, CCL5 recruits and polarizes macrophages to the M2 phenotype, enhancing tumor infiltration. Antagonizing CCL5 receptor, CCR5, or blocking activation of the downstream mTOR or ERK pathway, effectively suppresses HNSCC progression. Our study uncovers the ΔNp63/CCL5 as a key regulatory axis of HNSCC metastasis and proliferation, proposing novel therapeutic targets for this malignancy. Health sciences/Diseases/Cancer/Metastasis Biological sciences/Cancer/Metastasis Full Text Additional Declarations (Not answered) Supplementary Files SupplementaryMaterialsforCCL5ManuscriptLXS20260415.docx Supplementary data 260413WBXXXXXX.docx Original WB images Cite Share Download PDF Status: Under Review Version 1 posted Review # 1 received at journal 11 May, 2026 Review # 2 received at journal 23 Apr, 2026 Reviewer # 2 agreed at journal 22 Apr, 2026 Reviewer # 1 agreed at journal 21 Apr, 2026 Reviewers invited by journal 21 Apr, 2026 Submission checks completed at journal 18 Apr, 2026 First submitted to journal 16 Apr, 2026 Unknown event 16 Apr, 2026 Editor assigned by journal 15 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8549358","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":624239113,"identity":"5ee4765a-01d4-47e2-878a-ed4252f50142","order_by":0,"name":"Chenghua 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