{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:51:29Z","timestamp":1792122689968,"version":"4.4.0"},"reference-count":21,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with a poor prognosis. Surgical removal of the primary tumor and regional lymph nodes (LNs) remains the fundamental treatment for OSCC, although 40% of patients are negative for LN metastasis. The epithelial\u2013mesenchymal transition (EMT) plays a crucial role in OSCC progression by enabling epithelial cells to acquire mesenchymal traits, thereby facilitating migration and metastasis. Smad4, a tumor suppressor protein, is known to mediate EMT and is associated with poor prognosis and metastasis; however, its precise pro-metastatic role in OSCC via EMT remains unclear. Aims: We hypothesize that EMT and Smad4 could serve as practical diagnostic tools for personalized OSCC treatment. Methods: In this study, we analyzed 23 OSCC samples from Tzafon Medical Center, comparing the expression of Smad4 and EMT markers with clinical and histopathological data. Additionally, an OSCC cell model with and without Smad4 mutation was used to investigate tumor phenotypes, including proliferation and invasion, in relation to EMT markers. Results and Conclusion: Our findings reveal a strong correlation between EMT markers, Smad4 expression, and OSCC pathological staging, with the cell model further confirming the link between Smad4 and EMT markers. The combined influence of Smad4 and EMT markers on OSCC progression highlights their potential as diagnostic tools and as guides for personalized treatment strategies.<\/jats:p>","DOI":"10.3390\/cancers17111761","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T12:24:18Z","timestamp":1748003058000},"page":"1761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Interplay of SMAD4 and EMT in Oral Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4082-097X","authenticated-orcid":false,"given":"Shiraz","family":"Mozalbat","sequence":"first","affiliation":[{"name":"Molecular Biology of Oral Cancer Laboratory, Tzafon Medical Center, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysar","family":"Nashef","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Tzafon Medical Center, Faculty of Medicine, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseem","family":"Maalouf","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Tzafon Medical Center, Faculty of Medicine, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murad","family":"Abdol-Elraziq","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Tzafon Medical Center, Faculty of Medicine, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imad Abu","family":"El-naaj","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Tzafon Medical Center, Faculty of Medicine, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8038-5120","authenticated-orcid":false,"given":"Hagar","family":"Tadmor","sequence":"additional","affiliation":[{"name":"Molecular Biology of Oral Cancer Laboratory, Tzafon Medical Center, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2912-2920","authenticated-orcid":false,"given":"Yasmin","family":"Ghantous","sequence":"additional","affiliation":[{"name":"Molecular Biology of Oral Cancer Laboratory, Tzafon Medical Center, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","first-page":"2552","article-title":"TP53 Mutations and Survival in Squamous-Cell Carcinoma of the Head and Neck","volume":"357","author":"Poeta","year":"2007","journal-title":"Multicent. Study"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1002\/ijc.33352","article-title":"Epithelial-to-mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities","volume":"148","author":"Ling","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1002\/hed.21630","article-title":"Prognostic impact of different TNM-based stage groupings for oral squamous cell carcinoma","volume":"33","author":"Kreppel","year":"2011","journal-title":"Head Neck"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3322\/caac.21388","article-title":"The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more \u2018personalized\u2019 approach to cancer staging","volume":"67","author":"Amin","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.oooo.2019.10.012","article-title":"Neck nodal recurrence and survival of clinical T1-2 N0 oral squamous cell carcinoma in comparison of elective neck dissection versus observation: A meta-analysis","volume":"129","author":"Cai","year":"2020","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/nrm3758","article-title":"Molecular mechanisms of epithelial-mesenchymal transition","volume":"15","author":"Lamouille","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s10585-014-9690-1","article-title":"Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma","volume":"32","author":"Morand","year":"2015","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1590\/1678-775720140187","article-title":"Expression of epithelial-mesenchymal transition markers at the invasive front of oral squamous cell carcinoma","volume":"23","author":"Costa","year":"2015","journal-title":"J. Appl. Oral Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1007\/s00018-011-0735-1","article-title":"Vimentin in cancer and its potential as a molecular target for cancer therapy","volume":"68","author":"Satelli","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/s41580-018-0007-0","article-title":"Contextual determinants of TGF\u03b2 action in development, immunity and cancer","volume":"19","author":"David","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Xia, R.H., Song, X.M., Wang, X.J., Li, J., and Mao, L. (2013). The Combination of SMAD4 Expression and Histological Grade of Dysplasia Is a Better Predictor for the Malignant Transformation of Oral Leukoplakia. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066794"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1007\/s12032-014-0970-z","article-title":"Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC","volume":"31","author":"Zhai","year":"2014","journal-title":"Med. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Park, M., Kim, D., Ko, S., Kim, A., Mo, K., and Yoon, H. (2022). Breast Cancer Metastasis: Mechanisms and Therapeutic Implications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126806"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1007\/s10585-008-9170-6","article-title":"Epithelial mesenchymal transition traits in human breast cancer cell lines","volume":"25","author":"Blick","year":"2008","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1177\/1066896916654763","article-title":"Immunoexpression of Epithelial Mesenchymal Transition Proteins E-Cadherin, \u03b2-Catenin, and N-Cadherin in Oral Squamous Cell Carcinoma","volume":"24","author":"Angadi","year":"2016","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kaur, J., Sawhney, M., DattaGupta, S., Shukla, N.K., Srivastava, A., Walfish, P.G., and Ralhan, R. (2013). Clinical Significance of Altered Expression of \u03b2-Catenin and E-Cadherin in Oral Dysplasia and Cancer: Potential Link with ALCAM Expression. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067361"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.oraloncology.2014.06.005","article-title":"\u03b2-Catenin in oral cancer: An update on current knowledge","volume":"50","author":"Scully","year":"2014","journal-title":"Oral Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.oraloncology.2012.05.011","article-title":"Epithelial to mesenchymal transition (EMT) biomarkers - E-cadherin, beta-catenin, APC and Vimentin\u2014In oral squamous cell carcinogenesis and transformation","volume":"48","author":"Chaw","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.29245\/2578-2967\/2019\/2.1141","article-title":"The Promising Role of TGF-\u03b2\/SMAD4 in Pancreatic Cancer: The future targeted therapy","volume":"3","author":"Ahmed","year":"2019","journal-title":"J. Cancer Treat. Diagn."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10735-018-9763-6","article-title":"Smad4 and epithelial\u2013mesenchymal transition proteins in colorectal carcinoma: An immunohistochemical study","volume":"49","author":"Ioannou","year":"2018","journal-title":"J. Mol. Histol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/11\/1761\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:39:31Z","timestamp":1760031571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/11\/1761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,23]]},"references-count":21,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cancers17111761"],"URL":"https:\/\/doi.org\/10.3390\/cancers17111761","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,23]]}}}