Tspan12, a member of the tetraspanin family, has diverse functions. It is involved in the renin-angiotensin system and acts as a negative regulator of aldosterone production [2]. In the retina, it serves as a Norrin co-receptor, interacting with FZD4 and Norrin (NDP) to mediate angiogenesis, and is linked to familial exudative vitreoretinopathy (FEVR) [8].

In non-small cell lung cancer (NSCLC), Tspan12 functions as a tumor suppressor. miR-196b-5p, regulated by QKI-5, directly targets Tspan12, and down-regulation of Tspan12 promotes tumor progression [1]. In ovarian cancer, overexpression of Tspan12 accelerates cell proliferation and colony formation, and knockdown decreases these processes, with cyclins and cyclin-dependent kinases involved in the downstream cell cycle regulation [4]. In small cell lung cancer (SCLC), Tspan12 promotes chemoresistance and proliferation, and its elevation in specimens correlates with poor pathologic stage and shorter survival time [6]. In eosinophilic esophagitis (EoE), lower Tspan12 expression in the esophageal endothelium is associated with fibrostenosis, and interleukin-13 reduces Tspan12 expression, which may contribute to tissue remodeling [5]. Mutations in Tspan12 cause FEVR, and in vitro studies show that mutant Tspan12 leads to decreased protein expression and disrupted Norrin/β-catenin signaling [3,7].

In conclusion, Tspan12 plays crucial roles in multiple biological processes and diseases. In cancer, its role varies depending on the type, either as a tumor suppressor in NSCLC or promoting cancer cell proliferation and chemoresistance in other cancers. In the context of adrenal physiology, it regulates aldosterone production, and in the retina, it is essential for normal angiogenesis. Studies of Tspan12, especially through in vivo models, help us understand its function in disease development, providing potential targets for treatment.

References:

1. Liang, Guang, Meng, Wei, Huang, Xiangjie, Croce, Carlo M, Cui, Ri. 2020. miR-196b-5p-mediated downregulation of TSPAN12 and GATA6 promotes tumor progression in non-small cell lung cancer. In Proceedings of the National Academy of Sciences of the United States of America, 117, 4347-4357. doi:10.1073/pnas.1917531117. https://pubmed.ncbi.nlm.nih.gov/32041891/

2. Gong, Siyuan, Tetti, Martina, Kemter, Elisabeth, Reincke, Martin, Williams, Tracy Ann. 2022. TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas. In Hypertension (Dallas, Tex. : 1979), 80, 440-450. doi:10.1161/HYPERTENSIONAHA.122.19783. https://pubmed.ncbi.nlm.nih.gov/36458545/

3. Ju, Yuqiao, Chen, Tianhui, Ruan, Lu, Chang, Qing, Huang, Xin. 2024. Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy. In Human genomics, 18, 22. doi:10.1186/s40246-024-00589-6. https://pubmed.ncbi.nlm.nih.gov/38424652/

4. Ji, Guohua, Liang, Hongbin, Wang, Falin, Fu, Songbin, Cui, Xiaobo. . TSPAN12 Precedes Tumor Proliferation by Cell Cycle Control in Ovarian Cancer. In Molecules and cells, 42, 557-567. doi:10.14348/molcells.2019.0015. https://pubmed.ncbi.nlm.nih.gov/31362470/

5. Shoda, Tetsuo, Wen, Ting, Caldwell, Julie M, Furuta, Glenn T, Rothenberg, Marc E. 2021. Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell-Fibroblast Crosstalk. In Gastroenterology, 162, 439-453. doi:10.1053/j.gastro.2021.10.016. https://pubmed.ncbi.nlm.nih.gov/34687736/

6. Ye, Minting, Wei, Ting, Wang, Qiongyao, Guo, Linlang, Zhu, Weiliang. 2017. TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495. In Biochemical and biophysical research communications, 486, 349-356. doi:10.1016/j.bbrc.2017.03.044. https://pubmed.ncbi.nlm.nih.gov/28302484/

7. Wang, You, Lai, Yanting, Jiang, Zhaoxin, Li, Songshan, Ding, Xiaoyan. 2023. Five novel dysfunctional variants in the TSPAN12 gene in familial exudative vitreoretinopathy. In Experimental eye research, 234, 109574. doi:10.1016/j.exer.2023.109574. https://pubmed.ncbi.nlm.nih.gov/37451565/

8. Lai, Maria B, Zhang, Chi, Shi, Jianli, Chen, Zhe, Junge, Harald J. . TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling. In Cell reports, 19, 2809-2822. doi:10.1016/j.celrep.2017.06.004. https://pubmed.ncbi.nlm.nih.gov/28658627/