HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer.
HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer.
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DOI：
10.18632/oncotarget.17887
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Kim HC
中科院分区：
文献类型：
--
作者：
Jung YS;Najy AJ;Huang W;Sethi S;Snyder M;Sakr W;Dyson G;Hüttemann M;Lee I;Ali-Fehmi R;Franceschi S;Struijk L;Kim HE;Kato I;Kim HC
与HPV阴性患者相比，HPV阳性口咽癌患者的局部复发率显著降低，总生存率较高，尤其是在接受放射治疗的患者中。本研究的目的是探讨HPV阴性和HPV阳性头颈部鳞状细胞癌（HNSCC）放射敏感性差异的分子机制。在这里，我们表明，HPV阴性HNSCC细胞表现出增加的葡萄糖代谢所证明的乳酸盐的生产增加，而HPV阳性HNSCC细胞有效地利用线粒体呼吸所证明的增加的耗氧量。HPV阴性细胞表达HIF 1 α及其下游葡萄糖代谢介质，如高水平的己糖激酶II（HKII）和碳酸酐酶IX（CAIX），而细胞色素c氧化酶（考克斯）的表达水平在HPV阳性的HNSCC中明显较高。此外，与HPV阳性细胞相比，HPV阴性HNSCC中丙酮酸脱氢酶激酶（PDK）的表达水平高得多，所述丙酮酸脱氢酶激酶抑制丙酮酸脱氢酶活性，从而防止丙酮酸进入线粒体三羧酸（TCA）循环。重要的是，PDK抑制剂二氯乙酸盐有效地使HPV阴性细胞对辐射敏感。最后，我们发现扁桃体位置和HPV阳性之间的积极相互作用的考克斯强度和考克斯/HKII指数比值，通过免疫组化分析确定。随着考克斯表达的增加，扁桃体HNSCC患者的总体生存率显著提高。综上所述，本研究提供了HPV驱动与自发或化学诱导的口咽癌之间对放射治疗的差异反应的机制基础的分子见解。
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption. HPV-negative cells express HIF1α and its downstream mediators of glucose metabolism such as hexokinase II (HKII) and carbonic anhydrase IX (CAIX) at higher levels, while the expression level of cytochrome c oxidase (COX) was noticeably higher in HPV-positive HNSCC. In addition, the expression levels of pyruvate dehydrogenase kinases (PDKs), which inhibit pyruvate dehydrogenase activity, thereby preventing entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle, were much higher in HPV-negative HNSCC compared to those in HPV-positive cells. Importantly, a PDK inhibitor, dichloroacetate, effectively sensitized HPV-negative cells to irradiation. Lastly, we found positive interactions between tonsil location and HPV positivity for COX intensity and COX/HKII index ratio as determined by immunohistochemical analysis. Overall survival of patients with HNSCC at the tonsil was significantly improved with an increased COX expression. Taken together, the present study provides molecular insights into the mechanistic basis for the differential responses to radiotherapy between HPV-driven vs. spontaneous or chemically induced oropharyngeal cancer.
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影响因子：
11.5
作者：
Meijer, Tineke W. H.;Kaanders, Johannes H. A. M.;Bussink, Johan
通讯作者：
Bussink, Johan
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5.6
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DOI：
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发表时间：
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影响因子：
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作者：
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影响因子：
10.3
作者：
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