Broad Phenotypic Changes Associated with Gain of Radiation Resistance in Head and Neck Squamous Cell Cancer
Broad Phenotypic Changes Associated with Gain of Radiation Resistance in Head and Neck Squamous Cell Cancer
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DOI：
10.1089/ars.2013.5690
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发表时间：
2014-07-10
影响因子：
6.6
通讯作者：
Furdui, Cristina M.
中科院分区：
文献类型：
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作者：
Bansal, Nidhi;Mims, Jade;Furdui, Cristina M.
目的：尽管治疗方式有所改进，出现了新的治疗方法，但抗辐射的核心问题仍然是癌症治疗中的一个重大挑战。为了便于识别引起电离辐射防护的分子因素，我们开发了头颈部鳞状细胞癌(HNSCC)辐射抗性的匹配模型，并使用定量质谱学和互补分析表征了其特性。结果：蛋白质组学数据的功能网络分析表明，DNA复制和碱基切除修复、细胞外基质-受体相互作用、细胞周期、焦点黏附和肌动蛋白细胞骨架的调节在耐药(RSCC-61)HNSCC细胞中显著上调或下调。在RSCC-61中上调的蛋白质包括一些细胞角蛋白、脂肪酸合成酶和抗氧化蛋白。此外，与亲代放射敏感的SCC-61细胞相比，RSCC-61细胞显示出两个意想不到的特征：(I)RSCC-61细胞对表皮生长因子受体的小分子抑制剂Erlotinib的敏感性增加；(Ii)蛋白质标记物的表达和功能分析(如Vimentin，迁移)证实了RSCC-61细胞从间充质向上皮细胞的转变。创新：这里提出的辐射抗性匹配模型表明，多个信号和代谢途径汇聚在一起产生RSCC-61表型，这表明抗氧化系统作为RSCC-61抵抗电离辐射的主要调节系统的功能，这一现象被对HNSCC肿瘤样本的分析进一步证实。结论：RSCC-61/SCC-61模型为在临床前环境下研究联合放射治疗和厄洛替尼的氧化还原调节机制提供了机会。
Aims: The central issue of resistance to radiation remains a significant challenge in the treatment of cancer despite improvements in treatment modality and emergence of new therapies. To facilitate the identification of molecular factors that elicit protection against ionizing radiation, we developed a matched model of radiation resistance for head and neck squamous cell cancer (HNSCC) and characterized its properties using quantitative mass spectrometry and complementary assays. Results: Functional network analysis of proteomics data identified DNA replication and base excision repair, extracellular matrix-receptor interaction, cell cycle, focal adhesion, and regulation of actin cytoskeleton as significantly up- or downregulated networks in resistant (rSCC-61) HNSCC cells. Upregulated proteins in rSCC-61 included a number of cytokeratins, fatty acid synthase, and antioxidant proteins. In addition, the rSCC-61 cells displayed two unexpected features compared with parental radiation-sensitive SCC-61 cells: (i) rSCC-61 had increased sensitivity to Erlotinib, a small-molecule inhibitor of epidermal growth factor receptor; and (ii) there was evidence of mesenchymal-toepithelial transition in rSCC-61, confirmed by the expression of protein markers and functional assays (e.g., Vimentin, migration). Innovation: The matched model of radiation resistance presented here shows that multiple signaling and metabolic pathways converge to produce the rSCC-61 phenotype, and this points to the function of the antioxidant system as a major regulator of resistance to ionizing radiation in rSCC-61, a phenomenon further confirmed by analysis of HNSCC tumor samples. Conclusion: The rSCC-61/SCC-61 model provides the opportunity for future investigations of the redox-regulated mechanisms of response to combined radiation and Erlotinib in a preclinical setting.