Fractionated irradiation induces radioresistant oral carcinoma cells with enhanced malignant phenotypes

IF 2.2 4区 医学 Q2 DENTISTRY, ORAL SURGERY & MEDICINE Archives of oral biology Pub Date : 2024-05-03 DOI:10.1016/j.archoralbio.2024.105988
Yangfan Liu , Tongxu Sun , Jin Yang, Jingjing Luo, Hongmei Zhou
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Abstract

Objective

The fact that certain oral carcinoma patients experience radiotherapy failure implies that a more radioresistant and aggressive phenotype of surviving cancer cells potentially occurs during treatment. Our study aimed to establish radioresistant oral cancer cells through a fractionated irradiation protocol that mimics clinically relevant radiotherapy dosing strategies and to investigate all-round alterations in the malignant phenotype.

Methods

Radioresistant oral carcinoma cells were generated by exposing Cal27 and Detroit 562 cells to 60 Gy radiation in 10 dose-escalating fractions and verified by cell immunofluorescence. Specific markers related to the epithelial–mesenchymal transition (EMT) process and the cancer stem cell (CSC) phenotype were assessed by Western blotting. Cell invasion and migration were evaluated using Matrigel-coated transwell and wound healing assays, respectively. Nontargeted metabolomics was used to mechanistically delineate the potential metabolic patterns linked to EMT and CSCs; the CSC phenotype was also examined by sphere formation assays and cell immunofluorescence.

Results

Radioresistant oral carcinoma cell lines were successfully established and validated. These cells exhibited enhanced EMT and increase in both cell invasion and migration. These radioresistant cells further demonstrated a high metabolic profile, notably marked by lipid metabolism reprogramming and functional enrichment of ATP-binding cassette (ABC) transporters. Consistently, enhanced CSC phenotype in radioresistant cells was confirmed by elevated expression of stemness markers and increased sphere-forming capacity.

Conclusion

Radioresistant oral carcinoma cells subjected to fractionated radiation exhibit an augmented malignant phenotype. The metabolic characteristics linked to enhanced EMT and CSC phenotypes provide potential targets for improving radiotherapy in oral carcinoma.

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分次照射诱导具有放射耐受性的口腔癌细胞,并增强其恶性表型
目的 某些口腔癌患者放疗失败,这意味着在治疗过程中,存活的癌细胞可能会出现更具放射抗性和侵袭性的表型。我们的研究旨在通过模拟临床相关放疗剂量策略的分次辐照方案建立放射耐受性口腔癌细胞,并研究恶性表型的全面改变。方法通过将 Cal27 和 Detroit 562 细胞暴露于 60 Gy 放射线,分 10 次剂量递增产生放射耐受性口腔癌细胞,并通过细胞免疫荧光进行验证。通过 Western 印迹法评估了与上皮-间质转化(EMT)过程和癌症干细胞(CSC)表型相关的特定标记物。细胞侵袭和迁移分别通过Matrigel包被的透孔试验和伤口愈合试验进行评估。非靶向代谢组学用于从机理上阐明与 EMT 和 CSC 相关的潜在代谢模式;CSC 表型还通过球形成试验和细胞免疫荧光进行了检测。这些细胞表现出增强的 EMT 以及细胞侵袭和迁移的增加。这些抗放射细胞进一步表现出高代谢特征,特别是脂质代谢重编程和 ATP 结合盒(ABC)转运体的功能丰富。同样,干性标志物表达的升高和球形成能力的增强也证实了耐放射细胞中CSC表型的增强。与 EMT 和 CSC 表型增强相关的代谢特征为改善口腔癌放疗提供了潜在靶点。
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来源期刊
Archives of oral biology
Archives of oral biology 医学-牙科与口腔外科
CiteScore
5.10
自引率
3.30%
发文量
177
审稿时长
26 days
期刊介绍: Archives of Oral Biology is an international journal which aims to publish papers of the highest scientific quality in the oral and craniofacial sciences. The journal is particularly interested in research which advances knowledge in the mechanisms of craniofacial development and disease, including: Cell and molecular biology Molecular genetics Immunology Pathogenesis Cellular microbiology Embryology Syndromology Forensic dentistry
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