Igfbp6, insulin-like growth factor binding protein 6, is a member of the IGF binding protein (IGFBP) family. It is a specific inhibitor of insulin-like growth factor II (IGF-II) and is involved in multiple biological processes such as cell proliferation, apoptosis, and immune-escape [4,5]. It is associated with pathways like PI3K-Akt, TGF-β, and MVP-c-Jun N-terminal kinase (JNK)/nuclear factor kappa B (NF-κB) [1,4]. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In vascular-related studies, IGFBP6-deficient mice show aggravated diet-and disturbed flow (DF)-induced atherosclerosis, while endothelial-cell-specific IGFBP6-overexpressing mice are protected against atherosclerosis, indicating that endothelial IGFBP6 suppresses vascular inflammation and atherosclerosis [1]. In vascular smooth muscle cells (VSMCs), knocking down IGFBP6 in VSMCs significantly attenuates cell proliferation and induces S-phase arrest during the cell cycle, revealing its role in VSMC biological function [2]. In glioblastoma, lactate-induced IGFBP6 expression in microglia leads to immune-escape activation, and IGFBP6 can also regulate the expansion of chemoresistant glioblastoma cells [3,7]. In breast cancer, high expression of IGFBP6 is associated with a good prognosis, and its expression is negatively correlated with glucose metabolism-related genes [4]. In glioma, overexpression of IGFBP6 induces cell apoptosis and inhibits migration, and it can be an independent prognostic factor [5]. In nasopharyngeal carcinoma, exogenous expression of IGFBP6 inhibits cell proliferation and invasion, and knockdown activates the GSK3β/β-catenin/cyclin D1 pathway and enhances tumor growth and metastasis [6].

In conclusion, Igfbp6 plays essential roles in various biological processes and diseases. Through model-based research, especially KO/CKO mouse models, it has been shown to be involved in vascular inflammation and atherosclerosis, VSMC proliferation, tumor immune-escape, and cell apoptosis and migration in different cancers. Understanding the functions of Igfbp6 provides potential therapeutic targets for these diseases.

References:

1. Su, Meiming, Zhao, Wenqi, Jiang, Hui, Xu, Suowen, Weng, Jianping. 2025. Endothelial IGFBP6 suppresses vascular inflammation and atherosclerosis. In Nature cardiovascular research, 4, 145-162. doi:10.1038/s44161-024-00591-0. https://pubmed.ncbi.nlm.nih.gov/39794479/

2. Wang, Zhecun, Qi, Yunling, Wang, Rui, Li, Wen, Wang, Shenming. 2020. IGFBP6 regulates vascular smooth muscle cell proliferation and morphology via cyclin E-CDK2. In Journal of cellular physiology, 235, 9538-9556. doi:10.1002/jcp.29762. https://pubmed.ncbi.nlm.nih.gov/32529639/

3. Longhitano, Lucia, Vicario, Nunzio, Forte, Stefano, Li Volti, Giovanni, Tibullo, Daniele. 2022. Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma. In Cancer immunology, immunotherapy : CII, 72, 1-20. doi:10.1007/s00262-022-03215-3. https://pubmed.ncbi.nlm.nih.gov/35654889/

4. Lu, Hang, Yu, Xin, Xu, Zhiliang, Zhang, Yimin, Sun, Shengrong. . Prognostic Value of IGFBP6 in Breast Cancer: Focus on Glucometabolism. In Technology in cancer research & treatment, 23, 15330338241271998. doi:10.1177/15330338241271998. https://pubmed.ncbi.nlm.nih.gov/39275851/

5. Bei, Yuanqi, Huang, Qingfeng, Shen, Jianhong, Ji, Bin, Chen, JianGuo. 2016. IGFBP6 Regulates Cell Apoptosis and Migration in Glioma. In Cellular and molecular neurobiology, 37, 889-898. doi:10.1007/s10571-016-0426-4. https://pubmed.ncbi.nlm.nih.gov/27650075/

6. Chen, Qiuyan, Qin, Siyuan, Liu, Yang, Zhang, Jian, Lu, Yi. . IGFBP6 is a novel nasopharyngeal carcinoma prognostic biomarker. In Oncotarget, 7, 68140-68150. doi:10.18632/oncotarget.11886. https://pubmed.ncbi.nlm.nih.gov/27623076/

7. Oliva, Claudia R, Halloran, Brian, Hjelmeland, Anita B, Sarkaria, Jann N, Griguer, Corinne E. 2018. IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling. In Cell communication and signaling : CCS, 16, 61. doi:10.1186/s12964-018-0273-7. https://pubmed.ncbi.nlm.nih.gov/30231881/