Jin Yuxi, Qi Meng, Si Lulu, Shi Xiaojing, Cai Mingbo, Fu Hanlin, Liu Yana, Guo Ruixia
Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan, China.
Cancer Sci. 2025 Mar;116(3):656-672. doi: 10.1111/cas.16447. Epub 2025 Jan 6.
Endometrial cancer (EC) is a worldwide gynecologic malignancies, with a remarking increase of incidence and mortality rates in recent years. Growing evidence indicates that glucose metabolism reprogramming is the most representative metabolic signature of tumor cells and exploring its modulatory function in EC development will promote identifying potential EC therapeutic targets. IGFBP2 is an insulin-like growth factor binding protein which is closely associated with a variety of metabolic diseases. However, its biological role in EC and its effects on glucose metabolism remain unclear. In this study, we demonstrated that IGFBP2 was highly expressed in EC tissues and correlated with poor prognosis. Overexpression of IGFBP2 promoted proliferation and glycolysis in EC cells, whereas IGFBP2 knockdown had the opposite effect. Mechanistically, IGFBP2 directly interacted with PKM2, inducing weakened PKM2 protein degradation, and knockdown IGFBP2 expression prevented the translocation of PKM2 to the nucleus. Additionally, IGFBP2 expression was upregulated under the condition of hypoxia which directly regulated by transcriptional activation of HIF-1α. Finally, the role of the IGFBP2/PKM2/HIF-1α axis in EC tumor growth was confirmed in vivo using mouse xenograft models. Taken together, the current study identifies IGFBP2 as an upstream activator of PKM2-driven proliferation and glycolysis in EC cells, providing a promising therapeutic target for EC.
子宫内膜癌（EC）是一种全球范围内的妇科恶性肿瘤，近年来其发病率和死亡率显著上升。越来越多的证据表明，葡萄糖代谢重编程是肿瘤细胞最具代表性的代谢特征，探索其在EC发生发展中的调节功能将有助于确定潜在的EC治疗靶点。胰岛素样生长因子结合蛋白2（IGFBP2）是一种与多种代谢性疾病密切相关的胰岛素样生长因子结合蛋白。然而，其在EC中的生物学作用及其对葡萄糖代谢的影响仍不清楚。在本研究中，我们证明IGFBP2在EC组织中高表达，并与预后不良相关。IGFBP2的过表达促进了EC细胞的增殖和糖酵解，而敲低IGFBP2则产生相反的效果。机制上，IGFBP2直接与丙酮酸激酶M2（PKM2）相互作用，导致PKM2蛋白降解减弱，敲低IGFBP2表达可阻止PKM2向细胞核的转位。此外，在缺氧条件下IGFBP2表达上调，这是由缺氧诱导因子-1α（HIF-1α）的转录激活直接调控的。最后，利用小鼠异种移植模型在体内证实了IGFBP2/PKM2/HIF-1α轴在EC肿瘤生长中的作用。综上所述，本研究确定IGFBP2是EC细胞中PKM2驱动的增殖和糖酵解的上游激活因子，为EC提供了一个有前景的治疗靶点。
