Li Songyang, Liu Yongjie, Yin Xiaofeng, Yang Yao, Liu Xinjia, Qiu Jiaxing, Yang Qinglan, Li Yana, Tan Zhiguo, Peng Hongyan, Xiong Peiwen, Wu Shuting, Huang Lanlan, Wang Xiangyu, Liu Sulai, Gong Yuxing, Gao Yuan, Zhang Lingling, Wang Junping, Deng Yafei, Zhong Zhaoyang, Deng Youcai
Pediatrics Research Institute of Hunan Province, the Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha 410007, China.
Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing 400038, China.
Acta Pharm Sin B. 2025 Apr;15(4):1922-1937. doi: 10.1016/j.apsb.2025.02.034. Epub 2025 Mar 2.
The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.
Janus激酶/信号转导子和转录激活子（JAK-STAT）控制自然杀伤（NK）细胞的发育和细胞毒性功能，然而，长链非编码RNA（lncRNA）是否参与该途径仍不清楚。我们发现，miR155HG在活化的NK细胞中升高，并在NK92和诱导多能干细胞（iPSC）来源的NK（iPSC-NK）细胞中促进其增殖和效应功能，且不依赖其衍生的miR-155和微肽P155。机制上，miR155HG与miR-6756结合并解除其对JAK3表达的抑制，从而促进JAK-STAT途径并增强NK细胞增殖和功能。进一步研究发现，在细胞因子刺激下，STAT3直接与miR155HG启动子相互作用并诱导miR155HG转录。总体而言，我们鉴定出一种miR155HG介导的JAK-STAT信号正反馈环。我们的研究还将为改善NK细胞过继性转移治疗癌症领域，特别是iPSC来源的NK细胞中的NK细胞生成和效应功能提供一个关于miR155HG的有力靶点。
