FOXM1-Mediated Regulation of Reactive Oxygen Species and Radioresistance in Oral Squamous Cell Carcinoma Cells
FOXM1-Mediated Regulation of Reactive Oxygen Species and Radioresistance in Oral Squamous Cell Carcinoma Cells
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DOI：
10.1016/j.labinv.2022.100060
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发表时间：
2023-02-16
影响因子：
5
通讯作者：
Nakayama, Hideki
中科院分区：
文献类型：
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作者：
Takeshita, Hisashi;Yoshida, Ryoji;Nakayama, Hideki
放射抵抗是口腔鳞状细胞癌（OSCC）成功治疗的主要障碍。为了帮助克服这个问题，我们已经开发了临床相关的抗辐射（CRR）细胞系，通过随时间照射亲代细胞产生，这对OSCC研究是有用的。在本研究中，我们使用CRR细胞及其亲本细胞系进行基因表达分析，以探讨口腔鳞癌细胞辐射抗性的调控。基于CRR细胞和亲本细胞系在辐照后基因表达随时间的变化，选择叉头框M1（FOXM 1）用于进一步分析其在OSCC细胞系（包括CRR细胞系和临床标本）中的表达。我们抑制或上调FOXM 1在口腔鳞状细胞癌细胞系，包括CRR细胞系的表达，并在各种条件下检查放射敏感性，DNA损伤和细胞活力。还研究了调节放射耐受性的分子网络，特别是氧化还原途径，并将FOXM 1抑制剂的放射增敏作用作为潜在的治疗应用进行了研究。我们发现FOXM 1在正常人角质形成细胞中不表达，但在几种OSCC细胞系中表达。与亲代细胞系相比，CRR细胞中FOXM 1的表达上调。在异种移植模型和临床标本中，辐照后存活的细胞中FOXM 1表达上调。FOXM 1特异性小干扰RNA（siRNA）治疗增加了放射敏感性，而FOXM 1过表达降低了放射敏感性，DNA损伤在两种条件下都发生了显着改变，氧化还原相关分子和活性氧产生水平也发生了显着改变。用FOXM 1抑制剂硫链丝菌素治疗具有放射增敏作用，并克服了CRR细胞的放射耐受性。根据这些结果，FOXM 1介导的活性氧调节可能是一种新的治疗靶点，用于治疗放射抵抗性口腔鳞癌;因此，针对该轴的治疗策略可能会克服这种疾病的放射抵抗性。(c)2023年的走廊。爱思唯尔公司出版代表美国和加拿大病理学会。这是一篇在CC BY许可证下的开放获取文章（http：//creativecommons.org/licenses/by/4.0/）。
Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression in OSCC cell lines, including CRR cell lines and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell lines. The expression of FOXM1 was upre-gulated in CRR cells compared with that detected in the parental cell lines. In a xenograft model and clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific small interfering RNA (siRNA) treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions, as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.(c) 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).