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IGFBP5 is an ROR1 ligand promoting glio-blastoma invasion via ROR1/HER2-CREB signaling axis

Weiwei Lin, Rui Niu, Seong-Min Park, Yan Zou, Sung Soo Kim, Xue Xia, Songge Xing, Qingshan Yang, Xinhong Sun, Zheng Yuan , Shuchang Zhou, Dongya Zhang, Hyung Joon Kwon, Saewhan Park, Chan Il Kim, Harim Koo, Yang Liu, Haigang Wu, Meng Zheng, Heon Yoo, Bingyang Shi,* Jong Bae Park* & Jinlong Yin*

Nature Communications 2023,14,1578. (IF=17.694)

Abstract

Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target.


 
? 2017 河南大学-麦考瑞大学
生物医学联合创新中心
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河南省开封市
河南大学金明校区,生命科学学院
475004
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邮箱: jcbi@vip.henu.edu.cn
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