Cldn17-KO Mouse

Cldn17, a member of the claudin (CLDN) family, is a tight junction protein. As a paracellular channel-forming protein, it has an anion-selective channel function, and residues in its extracellular loops 1 and 2 are crucial for this function [4]. It is involved in maintaining blood-tissue barrier regulation, especially in the regulation of anion balance across these barriers [2,4].

In Cldn17 -/- mice, there are no breeding abnormalities, but newborn pups show delayed growth. Adult mice display electrolyte imbalance, oxidative stress, and kidney injury. RNA-sequencing reveals hyperactivation of signaling pathways and down-regulation of SOD1 expression in kidneys, indicating the importance of Cldn17 in maintaining electrolytes and reactive oxygen species across the blood-tissue barrier [2]. In oral cancer, down-regulation of Cldn17 is observed, and over-expressing it inhibits the invasion and migration of oral cancer cells by inhibiting epithelial-mesenchymal transition (EMT), suggesting it may act as a tumor suppressor [1]. In contrast, in hepatocellular carcinoma, increased Cldn17 expression promotes a malignant phenotype in hepatocytes via the Tyk2/Stat3 signaling pathway and is associated with poor prognosis [5]. In breast carcinomas, Cldn17 shows variable expression, and is significantly up-regulated at the mRNA level in tumors compared to normal breast tissue [6]. Also, in pancreatic adenocarcinoma, IgG-type autoantibodies against Cldn17, combined with CA19-9, may serve as non-invasive novel biomarkers for diagnosis [3,7].

In conclusion, Cldn17 plays essential roles in maintaining electrolyte balance and reactive oxygen species regulation in the body, especially in kidney function. Its dysregulation is associated with various cancers, such as oral, liver, breast, and pancreatic cancers. Studies using Cldn17 knockout mouse models have been instrumental in revealing its functions in physiological and pathological conditions, providing valuable insights into disease mechanisms and potential diagnostic and therapeutic targets.

References:

1. Xu, Ya-Ni, Deng, Ming-Si, Liu, Yun-Feng, Yao, Jun, Xiao, Zi-Yi. 2021. Tight junction protein CLDN17 serves as a tumor suppressor to reduce the invasion and migration of oral cancer cells by inhibiting epithelial-mesenchymal transition. In Archives of oral biology, 133, 105301. doi:10.1016/j.archoralbio.2021.105301. https://pubmed.ncbi.nlm.nih.gov/34781072/

2. Adil, Mir S, Parvathagiri, Varun, Verma, Arti, Narayanan, S Priya, Somanath, Payaningal R. 2022. Claudin-17 Deficiency in Mice Results in Kidney Injury Due to Electrolyte Imbalance and Oxidative Stress. In Cells, 11, . doi:10.3390/cells11111782. https://pubmed.ncbi.nlm.nih.gov/35681477/

3. Zhuang, Liping, Huang, Changjing, Ning, Zhouyu, Cheng, Chien-Shan, Meng, Zhiqiang. 2022. Circulating tumor-associated autoantibodies as novel diagnostic biomarkers in pancreatic adenocarcinoma. In International journal of cancer, 152, 1013-1024. doi:10.1002/ijc.34334. https://pubmed.ncbi.nlm.nih.gov/36274627/

4. Conrad, Marcel P, Piontek, Jörg, Günzel, Dorothee, Fromm, Michael, Krug, Susanne M. 2015. Molecular basis of claudin-17 anion selectivity. In Cellular and molecular life sciences : CMLS, 73, 185-200. doi:10.1007/s00018-015-1987-y. https://pubmed.ncbi.nlm.nih.gov/26194246/

5. Sun, Lemeng, Feng, Liangshu, Cui, Jiuwei. 2018. Increased expression of claudin-17 promotes a malignant phenotype in hepatocyte via Tyk2/Stat3 signaling and is associated with poor prognosis in patients with hepatocellular carcinoma. In Diagnostic pathology, 13, 72. doi:10.1186/s13000-018-0749-1. https://pubmed.ncbi.nlm.nih.gov/30219077/

6. Tőkés, Anna-Mária, Szász, Attila Marcell, Juhász, Eva, Salamon, Ferenc, Kulka, Janina. 2011. Expression of tight junction molecules in breast carcinomas analysed by array PCR and immunohistochemistry. In Pathology oncology research : POR, 18, 593-606. doi:10.1007/s12253-011-9481-9. https://pubmed.ncbi.nlm.nih.gov/22193974/

7. Liu, Yuqi, Gao, Yuyi, Wu, Yangxue, Wang, Keyan, Ye, Hua. . Autoantibodies as Potential Liquid Biopsy Biomarker in Detection of Pancreatic Cancer: A Diagnostic Test Accuracy Review and Meta-Analysis. In Scandinavian journal of immunology, 101, e70012. doi:10.1111/sji.70012. https://pubmed.ncbi.nlm.nih.gov/40185645/