IGFBP3 induced by the TGF-β/EGFRvIII transactivation contributes to the malignant phenotype of glioblastoma

Xuehua Zhang; Guoyan Wang; Yujiao Gong; Leilei Zhao; Ping Song; He Zhang; Yurui Zhang; Huanyu Ju; Xiaoyu Wang; Bin Wang; Huan Ren; Xiao Zhu; Yucui Dong

doi:10.1016/j.isci.2023.106639

IGFBP3 induced by the TGF-β/EGFRvIII transactivation contributes to the malignant phenotype of glioblastoma

iScience. 2023 Apr 10;26(5):106639. doi: 10.1016/j.isci.2023.106639. eCollection 2023 May 19.

Authors

Xuehua Zhang¹, Guoyan Wang², Yujiao Gong³, Leilei Zhao¹, Ping Song⁴, He Zhang⁵, Yurui Zhang¹, Huanyu Ju⁶, Xiaoyu Wang⁷, Bin Wang¹, Huan Ren⁸, Xiao Zhu⁹, Yucui Dong¹

Affiliations

¹ Department of Immunology, Binzhou Medical University, Yantai, Shandong 264003, China.
² Clinical Laboratory of Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264199, China.
³ Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China.
⁴ Department of Ophthalmology, Jiarun Hospital of Harbin, Harbin, Heilongjiang 150000, China.
⁵ Department of Immunology, Qiqihar Medical University, Qiqihar, Heilongjiang 161000, China.
⁶ Department of Immunology, Harbin Medical University, Harbin, Heilongjiang 150081, China.
⁷ Department of Neurology, Hongda Hospital, Jinxiang, Shandong 272200, China.
⁸ School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China.
⁹ School of Computer and Control Engineering, Yantai University, Yantai, Shandong 264005, China.

Abstract

Dual or multi-targets therapy targeting epidermal growth factor receptor variant III (EGFRvIII) and other molecular may relax the constraint for glioblastoma (GBM), putting forward the urgent requirement of finding candidate molecules. Here, the insulin-like growth factor binding protein-3 (IGFBP3) was considered a candidate, whereas the mechanisms of IGFBP3 production remain unclear. We treated GBM cells with exogenous transforming growth factor β (TGF-β) to simulate the microenvironment. We found that TGF-β and EGFRvIII transactivation induced the activation of transcription factor c-Jun, which specifically bound to the promoter region of IGFBP3 through Smad2/3 and ERK1/2 pathways and promoted the production and secretion of IGFBP3. IGFBP3 knockdown inhibited the activation of TGF-β and EGFRvIII signals and the malignant behaviors triggered by them in vitro and in vivo. Collectively, our results indicated a positive feedback loop of p-EGFRvIII/IGFBP3 under administration of TGF-β, blocking IGFBP3 may be an additional target in EGFRvIII-expressing GBM-selective therapeutic strategy.

Keywords: Cancer; Molecular biology.