Hasmim Meriem, Janji Bassam, Khaled Mehdi, Noman Muhammad Zaeem, Louache Fawzia, Bordereaux Didier, Abderamane Abdou, Baud Veronique, Mami-Chouaib Fathia, Chouaib Salem
INSERM UMR1186, Immunologie Intégrative des Tumeurs, Equipe Labellisée Ligue contre le Cancer, Institut Gustave Roussy, 94800 Villejuif, France.
Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, 1526 Luxembourg City, Luxembourg.
J Immunol. 2017 Feb 15;198(4):1423-1428. doi: 10.4049/jimmunol.1600981. Epub 2017 Jan 16.
Hypoxia upregulates the core pluripotency factors NANOG, SOX2, and OCT4, associated with tumor aggressiveness and resistance to conventional anticancer treatments. We have previously reported that hypoxia-induced NANOG contributed in vitro to tumor cell resistance to autologous-specific CTL and in vivo to the in situ recruitment of immune-suppressive cells. In this study, we investigated the mechanisms underlying NANOG-mediated tumor cell resistance to specific lysis under hypoxia. We demonstrated the tumor-promoting effect of hypoxia on tumor initiation into immunodeficient mice using human non-small lung carcinoma cells. We next showed a link between NANOG and autophagy activation under hypoxia because inhibition of NANOG decreased autophagy in tumor cells. Chromatin immunoprecipitation and luciferase reporter assays revealed a direct binding of NANOG to a transcriptionally active site in a BNIP3L enhancer sequence. These data establish a new link between the pluripotency factor NANOG and autophagy involved in resistance to CTL under hypoxia.
缺氧会上调核心多能性因子NANOG、SOX2和OCT4，这些因子与肿瘤侵袭性及对传统抗癌治疗的抗性相关。我们之前曾报道，缺氧诱导的NANOG在体外导致肿瘤细胞对自体特异性CTL产生抗性，在体内导致免疫抑制细胞的原位募集。在本研究中，我们探究了缺氧条件下NANOG介导肿瘤细胞对特异性裂解产生抗性的潜在机制。我们使用人非小肺癌细胞证明了缺氧对免疫缺陷小鼠肿瘤起始的促进作用。接下来我们发现缺氧条件下NANOG与自噬激活之间存在联系，因为抑制NANOG会降低肿瘤细胞中的自噬。染色质免疫沉淀和荧光素酶报告基因检测显示NANOG直接结合到BNIP3L增强子序列中的一个转录活性位点。这些数据在多能性因子NANOG与缺氧条件下对CTL抗性所涉及的自噬之间建立了新的联系。
