Enhanced radiation sensitivity in HPV-positive head and neck cancer.
Enhanced radiation sensitivity in HPV-positive head and neck cancer.
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DOI：
10.1158/0008-5472.can-13-0587
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发表时间：
2013-08-01
期刊：
影响因子：
11.2
通讯作者：
Harari PM
中科院分区：
文献类型：
--
作者：
Kimple RJ;Smith MA;Blitzer GC;Torres AD;Martin JA;Yang RZ;Peet CR;Lorenz LD;Nickel KP;Klingelhutz AJ;Lambert PF;Harari PM
与人乳头瘤病毒−阴性(HPV−)肿瘤相比，人乳头瘤病毒相关头颈癌(HNC)患者的生存结果显著改善。到目前为止，研究这种差异的公开数据提供了相互矛盾的结果。我们利用体外和体内技术系统地研究了所有有效的HPV+HNC细胞系和一系列HPV−HNC细胞系的辐射敏感性。HPV+HNC表现出更高的固有辐射敏感性(平均SF2HPV−0.59vs.HPV+0.22，p<；0.0001)，与辐射后G2/M细胞周期停滞延长和细胞凋亡率增加(百分比变化0%vs.85%，p=0.002)相对应。全基因组微阵列被用来比较人乳头瘤病毒阳性和人乳头状瘤病毒−细胞系在辐射后24小时的基因表达。在HPV+细胞中，Tp53途径的多个基因表达上调(Z值4.9)，其中Tp53基因上调了4.6倍(p<；0.0001)。在永生化的人扁桃体上皮细胞中，表达HPV-16E6的细胞对辐射的敏感性增加，尽管E6对P53有降解作用。这表明，HPV+HNC细胞中功能正常的低水平P53可能被辐射激活，导致细胞死亡。与此相一致的是，siRNA更完全地敲除了TP53，导致了辐射抗性。这些结果为HPV+HNC相对于HPV−HNC更高的辐射敏感性提供了明确的证据和支持机制。这一问题正在一系列临床试验中进行积极的调查，这些试验试图根据HPV+HNC患者良好的总体生存结果来降低他们的放射(和化疗)。
Patients with human papillomavirus associated (HPV+) head and neck cancer (HNC) demonstrate significantly improved survival outcome compared to those with HPV− negative (HPV−) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV− HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV− 0.59 vs. HPV+ 0.22, p<0.0001), corresponding with a prolonged G2/M cell cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%, p=0.002). A genome-wide microarray was used to compare gene-expression 24 hours following radiation between HPV+ and HPV− cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6 fold increase in TP53 (p<0.0001). Using immortalized human tonsillar epithelial cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV− HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.