Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, PR China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, PR China.
Oncogene. 2020 Feb;39(7):1514-1526. doi: 10.1038/s41388-019-1083-0. Epub 2019 Oct 31.
Cancer immune surveillance is an important host protection process that inhibits carcinogenesis and maintains cellular homeostasis. The major histocompatibility complex class I-related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, by a combined bioinformatics prediction and experimental approach, we identify BCL11B 3'-UTR as a putative MICA and MICB ceRNA. We demonstrate in several human cell lines of different origins that the knockdown of BCL11B downregulates surface expression of MICA and MICB. Furthermore, we demonstrate miRNA dependency of BCL11B-mediated MICA and MICB regulation in Dicer knockdown HCT116 cells. In addition, MICA/B-targeting miRNAs (miR-17, miR-93, miR-20a, miR-20b, miR-106a, and miR-106b) repressed the expression of BCL11B by targeting its 3'-UTR. Moreover, we showed that the BCL11B knockdown-mediated downregulation of MICA/B resulted in reduced NK cell elimination in vitro and in vivo through reduced recognition of NKG2D. Of particular significance, BCL11B displays tumor-suppressive properties. The expression of BCL11B is downregulated in colon cancer tissues and associated with a reduced median survival of colon cancer patients. Taken together, our study revealed a new mechanism of BCL11B that prevents immune evasion of cancerous cells by upregulation of the NKG2D ligands MICA and MICB in a ceRNA manner.
癌症免疫监视是一种重要的宿主保护过程，可抑制癌变并维持细胞内稳态。主要组织相容性复合体Ⅰ类相关分子 A 和 B（MICA 和 MICB）是 NKG2D 配体，在肿瘤免疫监视中发挥重要作用。在本研究中，我们通过联合生物信息学预测和实验方法，确定了 BCL11B 3'-UTR 是 MICA 和 MICB 的潜在 ceRNA。我们在不同来源的几种人类细胞系中证明，BCL11B 的敲低会下调 MICA 和 MICB 的表面表达。此外，我们在 Dicer 敲低的 HCT116 细胞中证明了 BCL11B 介导的 MICA 和 MICB 调节对 miRNA 的依赖性。此外，MICA/B 靶向 miRNA（miR-17、miR-93、miR-20a、miR-20b、miR-106a 和 miR-106b）通过靶向其 3'-UTR 抑制 BCL11B 的表达。此外，我们表明 BCL11B 敲低介导的 MICA/B 下调导致 NK 细胞在体外和体内识别减少，从而减少 NKG2D 的识别。特别重要的是，BCL11B 具有肿瘤抑制特性。BCL11B 的表达在结肠癌组织中下调，并与结肠癌患者的中位生存期缩短相关。总之，我们的研究揭示了 BCL11B 的一种新机制，通过以 ceRNA 的方式上调 NKG2D 配体 MICA 和 MICB，防止癌细胞的免疫逃逸。
