人们常说，闪电从来不会两次击打同一个地方，当然如果该地方是避雷针除外。 一则对小鼠和人的最新研究报告显示，一种叫做UROD（尿卟啉原脱羧酶）的酶，其作用就像是癌细胞的避雷针，它会将放疗和化疗吸引到病变组织的特定的部位。

这些发现表明，UROD（它在本文章中第一次被看作是人类癌症中的一个关键性的角色）可帮助降低头颈部癌症患者的治疗副作用。头颈部癌症是全世界排第8位的最常见的癌症。 尽管在最近的几十年中所取得的诸多进展，与当前疗法有关的毒性副作用对许多患者来说已经产生了令人失望的后果。 头颈部肿瘤常常被发现位于重要器官的附近，因此，摧毁病变组织常常是一个棘手的挑战，因为它会导致威胁生命的各种状况。

Emma Ito及其同事在这里显示，将UROD作为标靶可选择性地增进对头颈部肿瘤的放疗和化疗的功效，同时也可将其对正常组织的毒性最小化。通过将治疗聚焦于组织的特别部位，病人可在不损害治疗功效的同时接受较低剂量的放疗和化疗药物。

UROD是一种参与生产一种叫做血红素分子的酶，而血红素对身体所有器官都是至关重要的（尽管它在血液、骨髓和肝脏中最丰富）。血红素是一类叫做血红素蛋白（其中包括在血液中携带氧气的蛋白：血红蛋白）的含铁蛋白中的主要成分。在小鼠中，阻断UROD基因的表达可增加癌细胞的死亡。对头颈部癌症组织样本的分析披露，肿瘤中的UROD浓度比正常组织显著要高。此外，研究人员确认，临床结果的改善与病人体内较低的UROD水平有关联，提示UROD可被用来预测病人对放疗的反应。文章的作者希望，UROD抑制剂将来可与放疗和化疗共同使用以降低副作用。

原文出处：

Sci Transl Med Vol. 3, Issue 67, DOI: 10.1126/scitranslmed.3001922

Uroporphyrinogen Decarboxylase Is a Radiosensitizing Target for Head and Neck Cancer

Emma Ito1,2, Shijun Yue2, Eduardo H. Moriyama2, Angela B. Hui2, Inki Kim2, Wei Shi2, Nehad M. Alajez2, Nirmal Bhogal2, GuoHua Li3, Alessandro Datti4,5, Aaron D. Schimmer1,2, Brian C. Wilson1,2, Peter P. Liu3, Daniel Durocher4, Benjamin G. Neel1,2, Brian O’Sullivan6,7, Bernard Cummings6,7, Rob Bristow1,2,6,7, Jeff Wrana4 and Fei-Fei Liu1,2,6,7,*

Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference–based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies.