한빛사논문
- 조회352
Weiwei Lin1,2,3,4,8, Rui Niu1,8, Seong-Min Park2,5,8, Yan Zou1,6,8, Sung Soo Kim2,8, Xue Xia1, Songge Xing1, Qingshan Yang1, Xinhong Sun1, Zheng Yuan1, Shuchang Zhou1, Dongya Zhang1, Hyung Joon Kwon7, Saewhan Park2, Chan Il Kim2, Harim Koo2, Yang Liu1, Haigang Wu1, Meng Zheng1, Heon Yoo2,3, Bingyang Shi1,6, Jong Bae Park1,2,3 & Jinlong Yin1,2
1Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China.
2Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea.
3Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea.
4Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea.
5Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141, Republic of Korea.
6Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
7Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea.
8These authors contributed equally: Weiwei Lin, Rui Niu, Seong-Min Park, Yan Zou, Sung Soo Kim.
Corresponding authors : Correspondence to Bingyang Shi, Jong Bae Park or Jinlong Yin.
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.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-06-02)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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