Abstract 887: Human microRNA-1250-5p targets IGFBP2 expression to regulate NK cell proliferation in hypoxia

Abstract Insulin-like growth factor binding protein 2 (IGFBP2) is involved in many physiological events, such as progression and survival of many types of cells. However, little is known about its role in human natural killer (NK) cells. Here, we report that miR-1250-5p regulates IGFBP2 expression, the most expressed gene in hypoxia-activated NK cells, thereby promotes NK cell proliferation in hypoxia. We found that IGFBP2 was not only highly expressed in cellular level, but also secreted from NK cells exposed to hypoxia. Both endogenous and secreted IGFBP2 are involved in NK cell proliferation in hypoxia. We identified miR-1250-5p directly binds to the 3’untranslated region of IGFBP2, and negatively regulates the expression of IGFBP2 in hypoxia-activated NK cells. Overexpression of miR-1250-5p has decreased NK cell proliferation, whereas inhibition of miR-1250-5p shows dramatically opposite effect. Clinical data showed that IGFBP2 expression was increased in tumor infiltrating NK cells compared with non-tumor infiltrating NK cells in patients of hepatocellular carcinoma (HCC), which is one of the representative tumors of hypoxia. We further demonstrated that miR-1250-5p negatively regulates IGFBP2 expression in tumor infiltrating NK cells of HCC patients. Furthermore, proliferation and survival markers, Ki-67, PCNA, cIAP1, cIAP2 as well as NK cell activating receptor, NKp44, were upregulated, whereas apoptotic and senescence markers, Bax, p53 and p16 were downregulated in tumor infiltrating NK cells in patients of HCC. These results indicate that the proliferation of NK cells in hypoxia is regulated by miR-1250-5p and its target gene IGFBP2, thereby enhancing therapeutic potential of NK cells against hypoxic tumor microenvironment. Citation Format: Kyung-Mi Lee, Minwha shin, Seon Ah Lim. Human microRNA-1250-5p targets IGFBP2 expression to regulate NK cell proliferation in hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 887.