Polycomb 介导的 miR-31 缺失激活了成人 T 细胞白血病和其他癌症中的 NIK 依赖性 NF-κB 通路。

Polycomb-mediated loss of miR-31 activates NIK-dependent NF-κB pathway in adult T cell leukemia and other cancers.

机构信息

Graduate School of Frontier Sciences, The University of Tokyo, Japan.

出版信息

Cancer Cell. 2012 Jan 17;21(1):121-35. doi: 10.1016/j.ccr.2011.12.015.

DOI:10.1016/j.ccr.2011.12.015

Abstract

Constitutive NF-κB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. Here, we report a pathway involving Polycomb-mediated miRNA silencing and NF-κB activation. We determine the miRNA signatures and reveal miR-31 loss in primary ATL cells. MiR-31 negatively regulates the noncanonical NF-κB pathway by targeting NF-κB inducing kinase (NIK). Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-κB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.

摘要

组成型 NF-κB 激活在由 HTLV-1 和其他癌症引起的成人 T 细胞白血病 (ATL) 中起因果作用。在这里，我们报告了一条涉及 Polycomb 介导的 miRNA 沉默和 NF-κB 激活的途径。我们确定了 miRNA 特征，并揭示了原发性 ATL 细胞中 miR-31 的缺失。miR-31 通过靶向 NF-κB 诱导激酶 (NIK) 负调控非经典 NF-κB 途径。因此，miR-31 的缺失会触发致癌信号。在 ATL 细胞中，miR-31 的水平受到表观遗传调控，异常上调的 Polycomb 蛋白以表观遗传方式导致 miR-31 的下调，从而导致 NF-κB 的激活和抗凋亡。此外，这个新出现的电路在其他癌症和受体起始的 NF-κB 级联中起作用。我们的研究结果提供了一个涉及表观遗传程序、炎症反应和致癌信号的视角。