Identification of a JAK-STAT-miR155HG positive feedback loop in regulating natural killer (NK) cells proliferation and effector functions.

Songyang LI; Yongjie LIU; Xiaofeng YIN; Yao YANG; Xinjia LIU; Jiaxing QIU; Qinglan YANG; Yana LI; Zhiguo TAN; Hongyan PENG; Peiwen XIONG; Shuting WU; Lanlan HUANG; Xiangyu WANG; Sulai LIU; Yuxing GONG; Yuan GAO; Lingling ZHANG; Junping WANG; Yafei DENG; Zhaoyang ZHONG; Youcai DENG

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Identification of a JAK-STAT-miR155HG positive feedback loop in regulating natural killer (NK) cells proliferation and effector functions.

Author: Songyang LI ¹ ; Yongjie LIU ¹ ; Xiaofeng YIN ² ; Yao YANG ² ; Xinjia LIU ¹ ; Jiaxing QIU ³ ; Qinglan YANG ¹ ; Yana LI ¹ ; Zhiguo TAN ⁴ ; Hongyan PENG ¹ ; Peiwen XIONG ¹ ; Shuting WU ¹ ; Lanlan HUANG ¹ ; Xiangyu WANG ¹ ; Sulai LIU ⁴ ; Yuxing GONG ⁵ ; Yuan GAO ⁵ ; Lingling ZHANG ⁶ ; Junping WANG ⁷ ; Yafei DENG ¹ ; Zhaoyang ZHONG ⁸ ; Youcai DENG ²
Author Information

1. 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.
2. Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing 400038, China.
3. Department of Biological Sciences, Columbia University, NY 10027, USA.
4. Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha 410005, China.
5. Translational Medicine Research Center, Shanxi Medical University, Taiyuan 030001, China.
6. Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
7. State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China.
8. The Fifth People's Hospital of Chongqing, Chongqing 400062, China.
Publication Type:Journal Article
Keywords: Competing endogenous RNA; JAK–STAT signaling pathway; NK cells; iPSC-NK cells; lncRNA; miR-6756; miR155HG
From: Acta Pharmaceutica Sinica B 2025;15(4):1922-1937
CountryChina
Language:English
Abstract: 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.