Institute of Medical Sciences, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
Cell Death Dis. 2018 May 1;9(5):490. doi: 10.1038/s41419-018-0542-9.
Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of 'stemness' genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Moreover, the radioresistant sublines display high levels of oncometabolites including α-ketoglutarate, and treatment of cancer cells with α-ketoglutarate enhances their stem-like properties in an AhR activation-dependent manner. IKKα directly activates stemness-related genes through an interaction with AhR as a bone fide chromatin modifier. Thus, AhR is functionally linked with cancer stem-like properties, and it drives tumorigenesis in the occurrence of radioresistance.
大多数癌症患者在疾病过程中接受放射治疗，而放射抗性的发生与预后不良有关。导致放射抗性发展过程中肿瘤发生潜能增强的分子途径知之甚少。在这里，我们证明芳基烃受体 (AhR) 在维持癌症干细胞样特性方面发挥着重要作用。AhR 通过直接靶向“干性”基因的启动子，如三磷酸腺苷结合盒亚家族 G 成员 2 (ABCG2) 基因，促进癌症干细胞样表型并驱动转移。此外，耐辐射亚系表现出高水平的致癌代谢物，包括α-酮戊二酸，并且用α-酮戊二酸处理癌细胞以 AhR 激活依赖性方式增强其干细胞样特性。IKKα 作为真正的染色质修饰物通过与 AhR 的相互作用直接激活与干性相关的基因。因此，AhR 与癌症干细胞样特性具有功能联系，并在放射抗性发生时驱动肿瘤发生。
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