Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado.
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Cancer Res. 2014 Dec 1;74(23):7024-36. doi: 10.1158/0008-5472.CAN-14-1346. Epub 2014 Oct 8.
Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Furthermore, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation, and this effect was suppressed by Hh inhibition. Our results demonstrate that Gli1 that is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy, where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy.
局部控制和晚期头颈部鳞状细胞癌（HNSCC）患者的总生存率仍然很差。 Hedgehog（Hh）信号通路与上皮间质转化有关，并且在这种疾病环境中，Hh 效应转录因子 Gli1 的激活是预后不良的因素。在这里，我们报告说，HNSCC 肿瘤前缘的 GLI1 表达增加会被辐射进一步增加，从而有助于治疗抑制。用环巴胺阻断 Hh 通路可抑制 GLI1 的激活并增强肿瘤对放疗的敏感性。此外，放射治疗诱导的 GLI1 表达部分是由 mTOR/S6K1 途径介导的。暴露于放射治疗的基质促进了肿瘤的快速再增殖，而这种作用被 Hh 抑制所抑制。我们的研究结果表明，在 HNSCC 中肿瘤-基质交界处上调的 Gli1 被放射治疗上调，这有助于基质介导的耐药性，并且 Hh 抑制剂提供了一种合理的策略来逆转这一过程，使 HNSCC 对放疗敏感。
