Itgbl1, or Integrin beta-like 1, is a secreted extracellular matrix protein. It is involved in multiple signaling pathways, such as TNFAIP3-mediated NF-κB, AKT, TGF-β-Smad2/3, and Wnt signaling pathways [1,3,5,6,7,9,10]. Itgbl1 plays a crucial role in various biological processes and diseases, especially in cancer metastasis, immune regulation, and tissue fibrosis [1,2,3,4,5,6,7,9,10]. Genetic models like gene knockout (KO) or conditional knockout (CKO) mouse models can be valuable in further exploring its functions.

In cancer, Itgbl1 has been extensively studied. In a colorectal cancer (CRC) model, primary tumors release Itgbl1-rich extracellular vesicles to activate fibroblasts in remote organs, promoting pre-metastatic niche formation and metastatic cancer growth via the TNFAIP3-mediated NF-κB signaling pathway [1]. In melanoma, Itgbl1 acts as an immunomodulator, inhibiting natural killer cells cytotoxicity and favoring tumor development [2]. In gastric cancer, Itgbl1 promotes cell proliferation, invasion, and anoikis resistance through the AKT/FBLN2 axis [5,6]. In pancreatic cancer, Itgbl1 promotes cancer progression through the TGF-β/Smad pathway and is transcriptionally inhibited by JDP2 [7]. In prostate cancer, Itgbl1 promotes epithelial-mesenchymal transition (EMT), invasion, and migration by activating the NF-κB signaling pathway [10]. In heart failure, Itgbl1 mediates fibroblast-cardiomyocyte crosstalk to promote cardiac fibrosis and hypertrophy, and its knockdown in transverse aortic constriction (TAC) mice blunts cardiac fibrosis, hypertrophy, and improves cardiac function [3]. In addition, in acute myeloid leukemia, hypermethylation of Itgbl1 is associated with poor prognosis, and demethylation can increase its expression [8]. In CRC, Itgbl1 is related to metastasis and is associated with the Wnt signaling pathway [9].

In conclusion, Itgbl1 is a key protein involved in multiple signaling pathways, playing important roles in cancer metastasis, immune regulation, and tissue fibrosis. Studies using KO/CKO mouse models, like in the case of cardiac fibrosis and hypertrophy, have provided insights into its role in specific disease areas, helping to understand the underlying mechanisms and potentially offering new therapeutic targets.

References:

1. Ji, Qing, Zhou, Lihong, Sui, Hua, Wang, Yan, Li, Qi. 2020. Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. In Nature communications, 11, 1211. doi:10.1038/s41467-020-14869-x. https://pubmed.ncbi.nlm.nih.gov/32139701/

2. Cheli, Yann, Tulic, Meri K, El Hachem, Najla, Bertolotto, Corine, Ballotti, Robert. 2021. ITGBL1 is a new immunomodulator that favors development of melanoma tumors by inhibiting natural killer cells cytotoxicity. In Molecular cancer, 20, 12. doi:10.1186/s12943-020-01306-2. https://pubmed.ncbi.nlm.nih.gov/33413419/

3. Chen, XiaoQiang, Li, XinTao, Wu, XiaoYu, Li, Jun, Cai, LiDong. . Integrin beta-like 1 mediates fibroblast-cardiomyocyte crosstalk to promote cardiac fibrosis and hypertrophy. In Cardiovascular research, 119, 1928-1941. doi:10.1093/cvr/cvad104. https://pubmed.ncbi.nlm.nih.gov/37395147/

4. Zhao, Jingling, Yang, Shuai, Xu, Yingbin, Shu, Bin, Qi, Shaohai. 2023. Mechanical pressure-induced dedifferentiation of myofibroblasts inhibits scarring via SMYD3/ITGBL1 signaling. In Developmental cell, 58, 1139-1152.e6. doi:10.1016/j.devcel.2023.04.014. https://pubmed.ncbi.nlm.nih.gov/37192621/

5. Yin, Feng-Yan, Qi, Huan-Peng, Qiao, Hui, Lv, Xiao-Hong, Tan, Hai-Hua. 2021. ITGBL1 promotes gastric cancer cell proliferation and invasion via Akt signal pathway. In Frontiers in bioscience (Landmark edition), 26, 682-691. doi:. https://pubmed.ncbi.nlm.nih.gov/33049688/

6. Shen, Kanger, Xia, Wei, Wang, Kun, Shi, Tongguo, Li, Rui. . ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis. In Journal of cellular and molecular medicine, 28, e18113. doi:10.1111/jcmm.18113. https://pubmed.ncbi.nlm.nih.gov/38332530/

7. Du, Tiancong, Zhang, Ke, Zhang, Zhongbo, Yu, Guilin, Xu, Yuanhong. 2022. ITGBL1 transcriptionally inhibited by JDP2 promotes the development of pancreatic cancer through the TGF-beta/Smad pathway. In Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 55, e11989. doi:10.1590/1414-431X2022e11989. https://pubmed.ncbi.nlm.nih.gov/35584452/

8. Lian, Xin-Yue, Ma, Ji-Chun, Zhou, Jing-Dong, Lin, Jiang, Qian, Jun. 2018. Hypermethylation of ITGBL1 is associated with poor prognosis in acute myeloid leukemia. In Journal of cellular physiology, 234, 9438-9446. doi:10.1002/jcp.27629. https://pubmed.ncbi.nlm.nih.gov/30317626/

9. Qi, Lu, Song, Fuyao, Ding, Yanqing. 2020. Regulatory Mechanism of ITGBL1 in the Metastasis of Colorectal Cancer. In Frontiers in oncology, 10, 259. doi:10.3389/fonc.2020.00259. https://pubmed.ncbi.nlm.nih.gov/32211321/

10. Li, Wenze, Li, Shuren, Yang, Jie, Yu, Miao, Zhang, Yadong. 2019. ITGBL1 promotes EMT, invasion and migration by activating NF-κB signaling pathway in prostate cancer. In OncoTargets and therapy, 12, 3753-3763. doi:10.2147/OTT.S200082. https://pubmed.ncbi.nlm.nih.gov/31190876/