IGSF3, the immunoglobulin superfamily member 3, is a membrane protein involved in multiple biological functions. It has been associated with cell-cell interactions, including homophilic cell adhesion, and might be involved in pathways related to ion homeostasis, cell motility, and tumor-associated signaling. Its functions are important in processes such as brain development, cell-mediated lung injury repair, and tumor progression [2,3,4].

In glioma, IGSF3 has been shown to interact with Kir4.1, suppressing potassium buffering. Tumors from seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells, and IGSF3-mediated potassium dysregulation drives glioma epileptiform activity and progression [1]. In melanoma, knockdown of Igsf3 in highly metastatic B16F10 cells significantly reduced lung metastasis, as IGSF3 promotes adhesion to vascular endothelial cells [3]. In hepatocellular carcinoma (HCC), silencing IGSF3 via lentiviral vector inhibited migration, invasion, and growth of HCC cell lines in vitro and in vivo, and over-expression promoted these processes, with IGSF3 activating the NF-κB pathway [5]. In a study on COPD, a patient with a breakpoint in the IGSF3 gene had markedly decreased expression, and IGSF3-deficient lymphoblastoids and lung structural cells showed altered functions related to cell adhesion, apoptosis, and wound repair [2].

In conclusion, IGSF3 is involved in diverse biological functions, especially in tumor-related processes like glioma progression, melanoma metastasis, and HCC development, as well as in cell-function-related processes in COPD. The use of gene-knockdown or knockout models in these studies has revealed its role in specific biological processes and disease conditions, providing insights into potential therapeutic targets.

References:

1. Curry, Rachel Naomi, Aiba, Isamu, Meyer, Jochen, Rao, Ganesh, Deneen, Benjamin. 2023. Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation. In Neuron, 111, 682-695.e9. doi:10.1016/j.neuron.2023.01.013. https://pubmed.ncbi.nlm.nih.gov/36787748/

2. Schweitzer, Kelly S, Jinawath, Natini, Yonescu, Raluca, Griffin, Constance A, Petrache, Irina. 2020. IGSF3 mutation identified in patient with severe COPD alters cell function and motility. In JCI insight, 5, . doi:10.1172/jci.insight.138101. https://pubmed.ncbi.nlm.nih.gov/32573489/

3. Guo, Yue, Kasai, Yutaka, Tanaka, Yuto, Ito, Takeshi, Murakami, Yoshinori. 2024. IGSF3 is a homophilic cell adhesion molecule that drives lung metastasis of melanoma by promoting adhesion to vascular endothelium. In Cancer science, 115, 1936-1947. doi:10.1111/cas.16166. https://pubmed.ncbi.nlm.nih.gov/38590281/

4. Cocito, Carolina, Xiang, Chaomei, Huang, Meng, Dahmane, Nadia, Greenfield, Jeffrey P. 2025. Immunoglobulin superfamily 3 (Igsf3) function is dispensable for brain development. In Scientific reports, 15, 6526. doi:10.1038/s41598-024-79349-4. https://pubmed.ncbi.nlm.nih.gov/39988603/

5. Sheng, Ping, Zhu, Huirong, Zhang, Wenxiu, Gu, Mingqi, Jiang, Hongchi. . The immunoglobulin superfamily member 3 (IGSF3) promotes hepatocellular carcinoma progression through activation of the NF-κB pathway. In Annals of translational medicine, 8, 378. doi:10.21037/atm.2020.02.14. https://pubmed.ncbi.nlm.nih.gov/32355822/