{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:28:20Z","timestamp":1753892900119,"version":"3.41.2"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:p>Oral cancer is a very aggressive disease with high rates of recurrence and metastasis. This study aimed at addressing how efficiently tongue cancer is suppressed after carbon ion irradiation. Here, the close relationship between upregulated expression of focal adhesion kinase (FAK) and high metastatic status in tongue squamous cell carcinoma patients was validated using bioinformatics and immunohistochemical analyses. Our data indicated that FAK suppression significantly enhanced the killing effect induced by irradiation in the tongue cancer cell line CAL27, as evidenced by increased apoptotic induction and reduced colony formation. More importantly, in FAK-deficient cells, carbon ion irradiation was shown to remarkably inhibit migration and invasion by delaying wound healing and slowing down motility. Further studies revealed that irradiation exposure caused disorganization of the actin cytoskeleton and reduced cell adhesive energy in FAK-deficient cells. Moreover, carbon ion treatment, in combination with FAK silencing, markedly blocked the phosphorylation levels of FAK, and paxillin, which partly contributed to the reduced motility of tongue squamous cell carcinoma CAL27 cells. Collectively, these results suggest that the prominent obstructing role of carbon ion irradiation in the growth inhibition and metastatic behavior of tumors, including attenuation of cell adhesiveness, motility, and invasiveness, could be distinctly modulated by FAK-mediated downstream pathways.<\/jats:p>","DOI":"10.3389\/fpubh.2021.631118","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T06:41:02Z","timestamp":1612334462000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Carbon Ion Irradiation Enhances the Anti-tumor Efficiency in Tongue Squamous Cell Carcinoma via Modulating the FAK Signaling"],"prefix":"10.3389","volume":"9","author":[{"given":"Qingzong","family":"Si","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhitong","family":"Bing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruihong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jizeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0213463","DOI":"10.1371\/journal.pone.0213463","article-title":"TNF-alpha-induced miR-450a mediates TMEM182 expression to promote oral squamous cell carcinoma motility","volume":"14","author":"Hsing","year":"2019","journal-title":"PLoS ONE."},{"key":"B2","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/j.bbrc.2015.01.062","article-title":"Tivantinib (ARQ-197) exhibits anti-tumor activity with down-regulation of FAK in oral squamous cell carcinoma","volume":"457","author":"Xi","year":"2015","journal-title":"Biochem Biophys Res Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1038\/bjc.2017.244","article-title":"Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis","volume":"117","author":"Almangush","year":"2017","journal-title":"Br J Cancer."},{"key":"B4","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1002\/ijc.30107","article-title":"Trends in oral cavity cancer incidence, mortality, survival and treatment in the Netherlands","volume":"139","author":"van Dijk","year":"2016","journal-title":"Int J Cancer."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1002\/hed.25640","article-title":"Sequential therapy of neoadjuvant biochemotherapy with cetuximab, paclitaxel, and cisplatin followed by cetuximab-based concurrent bioradiotherapy in high-risk locally advanced oral squamous cell carcinoma: Final analysis of a phase 2 clinical trial","volume":"41","author":"Yen","year":"2019","journal-title":"Head Neck."},{"key":"B6","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.jcms.2006.04.004","article-title":"Clinicopathological parameters and outcome of 245 patients operated for oral squamous cell carcinoma","volume":"34","author":"Garzino-Demo","year":"2006","journal-title":"J Craniomaxillofac Surg."},{"key":"B7","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.ijrobp.2018.09.013","article-title":"Predictors of early recurrence prior to planned postoperative radiation therapy for oral cavity squamous cell carcinoma and outcomes following salvage intensified radiation therapy","volume":"103","author":"Hosni","year":"2019","journal-title":"Int J Radiat Oncol Biol Phys."},{"key":"B8","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1016\/j.bbrc.2018.04.214","article-title":"Different mitochondrial fragmentation after irradiation with X-rays and carbon ions in HeLa cells and its influence on cellular apoptosis","volume":"500","author":"Jin","year":"2018","journal-title":"Biochem Biophys Res Commun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e0163896","DOI":"10.1371\/journal.pone.0163896","article-title":"Proteomic analysis implicates dominant alterations of RNA metabolism and the proteasome pathway in the cellular response to carbon-ion irradiation","volume":"11","author":"Wang","year":"2016","journal-title":"PLoS ONE."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1111\/cas.13323","article-title":"Enhancement of mTOR signaling contributes to acquired X-ray and C-ion resistance in mouse squamous carcinoma cell line","volume":"108","author":"Sato","year":"2017","journal-title":"Cancer Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s10585-017-9867-5","article-title":"Radiation therapy-induced metastasis: radiobiology and clinical implications","volume":"35","author":"Blyth","year":"2018","journal-title":"Clin Exp Metastas."},{"key":"B12","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.critrevonc.2014.05.006","article-title":"Radiation-enhanced cell migration\/invasion process: a review","volume":"92","author":"Moncharmont","year":"2014","journal-title":"Crit Rev Oncol Hematol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2999","DOI":"10.1007\/s00018-016-2210-5","article-title":"Effects of radiation on metastasis and tumor cell migration","volume":"73","author":"Vilalta","year":"2016","journal-title":"Cell Mol Life Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"391","DOI":"10.3389\/fonc.2019.00391","article-title":"The combination of particle irradiation with the hedgehog inhibitor GANT61 differently modulates the radiosensitivity and migration of cancer cells compared to X-ray irradiation","volume":"9","author":"Konings","year":"2019","journal-title":"Front Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"47738","DOI":"10.18632\/oncotarget.10281","article-title":"Carbon ion irradiation withstands cancer stem cells' migration\/invasion process in Head and Neck Squamous Cell Carcinoma (HNSCC)","volume":"7","author":"Moncharmont","year":"2016","journal-title":"Oncotarget."},{"key":"B16","doi-asserted-by":"publisher","first-page":"454","DOI":"10.3109\/09553002.2013.766769","article-title":"Impact of carbon ion irradiation on epidermal growth factor receptor signaling and glioma cell migration in comparison to conventional photon irradiation","volume":"89","author":"Stahler","year":"2013","journal-title":"Int J Radiat Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3390\/cancers11040468","article-title":"ROS production and distribution: a new paradigm to explain the differential effects of X-ray and carbon ion irradiation on cancer stem cell migration and invasion","volume":"11","author":"Wozny","year":"2019","journal-title":"Cancers."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e98448","DOI":"10.1371\/journal.pone.0098448","article-title":"Carbon ion radiation inhibits glioma and endothelial cell migration induced by secreted VEGF","volume":"9","author":"Liu","year":"2014","journal-title":"PLoS ONE."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1002\/cbin.10327","article-title":"Effects of carbon-ion beam irradiation on the angiogenic response in lung adenocarcinoma A549 cells","volume":"38","author":"Liu","year":"2014","journal-title":"Cell Biol Int."},{"key":"B20","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1177\/0960327114561664","article-title":"X-ray radiation promotes the metastatic potential of tongue squamous cell carcinoma cells via modulation of biomechanical and cytoskeletal properties","volume":"34","author":"Zheng","year":"2015","journal-title":"Hum Exp Toxicol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nrm1549","article-title":"Focal adhesion kinase: in command and control of cell motility","volume":"6","author":"Mitra","year":"2005","journal-title":"Nat Rev Mol Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1002\/hed.23038","article-title":"Focal adhesion kinase overexpression: correlation with lymph node metastasis and shorter survival in oral squamous cell carcinoma","volume":"35","author":"de Vicente","year":"2013","journal-title":"Head Neck."},{"key":"B23","doi-asserted-by":"publisher","first-page":"703","DOI":"10.3892\/mmr.2013.1555","article-title":"Knockdown of FAK inhibits the invasion and metastasis of Tca8113 cells in vitro","volume":"8","author":"Xiao","year":"2013","journal-title":"Mol Med Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.oraloncology.2008.05.021","article-title":"Expression of Bcl-2 family proteins and associated clinicopathologic factors predict survival outcome in patients with oral squamous cell carcinoma","volume":"45","author":"Camisasca","year":"2009","journal-title":"Oral Oncology."},{"key":"B25","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.radonc.2008.04.015","article-title":"Susceptible genes and molecular pathways related to heavy ion irradiation in oral squamous cell carcinoma cells","volume":"89","author":"Fushimi","year":"2008","journal-title":"Radiother Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/nnano.2017.45","article-title":"Imaging modes of atomic force microscopy for application in molecular and cell biology","volume":"12","author":"Dufrene","year":"2017","journal-title":"Nat Nanotechnol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.bbrc.2008.07.078","article-title":"AFM indentation study of breast cancer cells","volume":"374","author":"Li","year":"2008","journal-title":"Biochem Biophys Res Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/978-1-4939-8591-3_30","article-title":"Applications of atomic force microscopy for adhesion force measurements in mechanotransduction","volume":"1814","author":"Trache","year":"2018","journal-title":"Methods Mol Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"35131","DOI":"10.1038\/srep35131","article-title":"Carbon ion-irradiated hepatoma cells exhibit coupling interplay between apoptotic signaling and morphological and mechanical remodeling","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci Rep-Uk."},{"key":"B30","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s40496-014-0014-y","article-title":"Salivary biomarkers for detection of oral squamous cell carcinoma - current state and recent advances","volume":"1","author":"Yakob","year":"2014","journal-title":"Curr Oral Health Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1186\/1471-2407-10-365","article-title":"Deregulation of manganese superoxide dismutase (SOD2) expression and lymph node metastasis in tongue squamous cell carcinoma","volume":"10","author":"Liu","year":"2010","journal-title":"BMC Cancer."},{"key":"B32","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1097\/01.mlg.0000205141.54471.7f","article-title":"Genome-wide profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization","volume":"116","author":"Sparano","year":"2006","journal-title":"Laryngoscope."},{"key":"B33","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/j.ijrobp.2006.02.048","article-title":"Enhancement of SPHK1 in vitro by carbon ion irradiation in oral squamous cell carcinoma","volume":"65","author":"Higo","year":"2006","journal-title":"Int J Radiat Oncol Biol Phys."},{"key":"B34","doi-asserted-by":"publisher","first-page":"133","DOI":"10.4236\/ijmpcero.2014.33019","article-title":"Carbon-ion beams efficiently induce cell killing in X-ray resistant human squamous tongue cancer cells","volume":"3","author":"Takahashi","year":"2014","journal-title":"Int J Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.3892\/or.2015.3753","article-title":"Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro","volume":"33","author":"Storch","year":"2015","journal-title":"Oncol Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1016\/j.bbamcr.2014.06.007","article-title":"Radiation sensitization of tumor cells induced by shear stress: the roles of integrins and FAK","volume":"1843","author":"Luo","year":"2014","journal-title":"Biochim Biophys Acta."},{"key":"B37","doi-asserted-by":"publisher","first-page":"4643","DOI":"10.1158\/1078-0432.CCR-15-2785","article-title":"Proteomic profiling identifies PTK2\/FAK as a driver of radioresistance in hpv-negative head and neck cancer","volume":"22","author":"Skinner","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1089\/15230860260196290","article-title":"Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation","volume":"4","author":"Kasahara","year":"2002","journal-title":"Antioxid Redox Signal."},{"key":"B39","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.tjog.2020.03.012","article-title":"Genistein inhibits migration and invasion of cervical cancer HeLa cells by regulating FAK-paxillin and MAPK signaling pathways","volume":"59","author":"Chen","year":"2020","journal-title":"Taiwan J Obstet Gynecol."},{"key":"B40","unstructured":"Particle irradiation suppresses metastatic potential of cancer cells11320\n            OgataT\n            TeshimaT\n            KagawaK\n            HishikawaY\n            TakahashiY\n            KawaguchiA\n          15665286Cancer Res.652005"},{"key":"B41","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1158\/0008-5472.CAN-06-2162","article-title":"Bortezomib inhibits cell-cell adhesion and cell migration and enhances epidermal growth factor receptor inhibitor-induced cell death in squamous cell cancer","volume":"67","author":"Lorch","year":"2007","journal-title":"Cancer Res."}],"container-title":["Frontiers in Public Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2021.631118\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T06:41:11Z","timestamp":1612334471000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2021.631118\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,3]]},"references-count":41,"alternative-id":["10.3389\/fpubh.2021.631118"],"URL":"https:\/\/doi.org\/10.3389\/fpubh.2021.631118","relation":{},"ISSN":["2296-2565"],"issn-type":[{"type":"electronic","value":"2296-2565"}],"subject":[],"published":{"date-parts":[[2021,2,3]]},"article-number":"631118"}}