Tenascin-C (TNC), a large multimodular glycoprotein of the extracellular matrix, has diverse functions. It is a key regulator of processes like proliferation and apoptosis in cardiomyocytes. TNC is involved in multiple biological pathways, and its expression is tightly regulated. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying its functions [2].

In atherosclerosis, TNC, especially its C domain/isoform (TNC-C), is strongly overexpressed in atherosclerotic plaque active areas. Delivery vectors recognizing TNC-C, like G11, G11-iRGD, TN11, PL1, and PL3, are being investigated for atherosclerosis-targeted drug delivery. PL1 also targets the extra domain-B (EDB) of fibronectin, and some conjugate agents are in clinical trials. Additionally, ATN-RNA and IMA950 are being studied in clinical trials as therapeutic drugs and vaccines by targeting TNC, suggesting that targeting TNC could improve the success rate of atherosclerosis-targeted drugs [1].

In the context of cardiac injury post-myocardial infarction, METTL3, an m6A regulator, binds to m6A sites in TNC mRNA, enhancing its stability. This leads to increased TNC expression, which in turn results in cardiac fibrosis and cardiomyocyte apoptosis [2].

In gliomas, TDG-mediated active DNA demethylation of TNC promotes its expression, contributing to glioma development [3].

In ankylosing spondylitis, TNC is upregulated in ligament and entheseal tissues, and it promotes entheseal new bone formation by suppressing extracellular matrix adhesion force and activating the Hippo signalling pathway [4].

In myocardial ischemia/reperfusion injury, miR-495-3p targets TNC to regulate cardiomyocyte apoptosis and inflammation associated with Ca2+ overload [5].

In cancer, TNC is highly expressed in melanoma cell lines, implicated in melanoma progression, and is a promising target for diagnostic and therapeutic approaches in anti-cancer treatments [6,7].

In diabetic kidney disease, TNC promotes disease development through the TNC/TLR4/NF-κB/miR-155-5p inflammatory loop, and metformin can relieve inflammation and fibrosis by reducing TNC levels [8]. Also, TNC serum levels can serve as diagnostic biomarkers for colorectal cancer [9].

In conclusion, Tnc is involved in a wide range of biological processes and diseases. Studies using KO/CKO mouse models could potentially further clarify its role in these areas. Its functions span from being a regulator in cell proliferation and apoptosis to having implications in disease-specific pathways such as those related to atherosclerosis, cardiac injury, gliomas, ankylosing spondylitis, myocardial ischemia/reperfusion injury, cancer, and diabetic kidney disease. Understanding Tnc's functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Chen, Wujun, Wang, Yanhong, Ren, Chunling, Zhang, Daijun, Xing, Dongming. 2024. The role of TNC in atherosclerosis and drug development opportunities. In International journal of biological sciences, 20, 127-136. doi:10.7150/ijbs.89890. https://pubmed.ncbi.nlm.nih.gov/38164188/

2. Cheng, Hao, Li, Linnan, Xue, Junqiang, Ma, Jianying, Ge, Junbo. 2023. TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner. In Genes, 14, . doi:10.3390/genes14030591. https://pubmed.ncbi.nlm.nih.gov/36980863/

3. Xu, Hongyu, Long, Shengrong, Xu, Chengshi, Wei, Wei, Li, Xiang. 2024. TNC upregulation promotes glioma tumourigenesis through TDG-mediated active DNA demethylation. In Cell death discovery, 10, 347. doi:10.1038/s41420-024-02098-w. https://pubmed.ncbi.nlm.nih.gov/39090080/

4. Li, Zihao, Chen, Siwen, Cui, Haowen, Zhang, Zhongping, Liu, Hui. 2021. Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis. In Annals of the rheumatic diseases, 80, 891-902. doi:10.1136/annrheumdis-2021-220002. https://pubmed.ncbi.nlm.nih.gov/33858850/

5. Song, Wei, Qiu, Naiyan. 2022. MiR-495-3p depletion contributes to myocardial ischemia/reperfusion injury in cardiomyocytes by targeting TNC. In Regenerative therapy, 21, 380-388. doi:10.1016/j.reth.2022.08.007. https://pubmed.ncbi.nlm.nih.gov/36161101/

6. Dhaouadi, Sayda, Bouhaouala-Zahar, Balkiss, Orend, Gertraud. 2024. Tenascin-C targeting strategies in cancer. In Matrix biology : journal of the International Society for Matrix Biology, 130, 1-19. doi:10.1016/j.matbio.2024.04.002. https://pubmed.ncbi.nlm.nih.gov/38642843/

7. Shao, Hanshuang, Kirkwood, John M, Wells, Alan. . Tenascin-C Signaling in melanoma. In Cell adhesion & migration, 9, 125-30. doi:10.4161/19336918.2014.972781. https://pubmed.ncbi.nlm.nih.gov/25482624/

8. Zhou, Yang, Ma, Xiao-Yu, Han, Jin-Yu, Kang, Jia-Yi, Wang, Qiu-Yue. . Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop. In World journal of diabetes, 12, 19-46. doi:10.4239/wjd.v12.i1.19. https://pubmed.ncbi.nlm.nih.gov/33520106/

9. Zhou, Minze, Li, Maoyu, Liang, Xujun, Pei, Haiping, Chen, Yongheng. 2019. The Significance of Serum S100A9 and TNC Levels as Biomarkers in Colorectal Cancer. In Journal of Cancer, 10, 5315-5323. doi:10.7150/jca.31267. https://pubmed.ncbi.nlm.nih.gov/31632476/