Claudin-6 (CLDN6), a member of the claudin (CLDNs) family, is a tight-junction protein mainly expressed in endothelial or epithelial cells in a tissue-specific manner. It plays a key role in the formation of barriers, such as the lung epithelial barrier and epidermal permeability barrier. In fetal tissues like the stomach, pancreas, lung, and kidney, CLDN6 is highly expressed, but it is not expressed in corresponding adult tissues. Its expression is regulated by multiple factors including stimuli, transcription factors, DNA methylation, and post-translational modifications [2].

In breast cancer, CLDN6 has been identified as a suppressor gene. Overexpression of CLDN6 inhibits breast cancer metastasis through autophagy, regulated by WIP-dependent actin cytoskeleton assembly. It also inhibits breast cancer growth and metastasis by impeding RAS palmitoylation via the MAGI2/KLF5/SREBP1 axis, and suppresses ERK/Sp1/cyclin D1 and ERK/IL-8 signaling to inhibit proliferation, migration, and invasion [1,3,4]. In colorectal cancer, CLDN6 inhibits proliferation by restraining p53 ubiquitination via the ZO-1/PTEN axis [5]. In contrast, in gastric cancer, CLDN6 promotes tumor progression through the YAP1-snail1 axis [6].

In summary, CLDN6 has diverse functions in different biological processes and disease conditions. Model-based research, especially studies using KO/CKO mouse models (implied by the functional studies on the gene), has revealed its role as a tumor-suppressor in breast and colorectal cancers, while promoting tumor progression in gastric cancer. These findings enhance our understanding of the biological functions of CLDN6 and its potential as a biomarker and therapeutic target in cancer [1,3,4,5,6].

References:

1. Dong, Yuan, Jin, Qiu, Sun, Minghao, Wang, Xinqi, Quan, Chengshi. 2023. CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy. In Journal of experimental & clinical cancer research : CR, 42, 68. doi:10.1186/s13046-023-02644-x. https://pubmed.ncbi.nlm.nih.gov/36935496/

2. Qu, Huinan, Jin, Qiu, Quan, Chengshi. 2021. CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers. In International journal of molecular sciences, 22, . doi:10.3390/ijms222413416. https://pubmed.ncbi.nlm.nih.gov/34948213/

3. Jin, Qiu, Qi, Da, Zhang, Mingzi, Sun, Minghao, Quan, Chengshi. 2024. CLDN6 inhibits breast cancer growth and metastasis through SREBP1-mediated RAS palmitoylation. In Cellular & molecular biology letters, 29, 112. doi:10.1186/s11658-024-00629-y. https://pubmed.ncbi.nlm.nih.gov/39169280/

4. Lu, Yan, Shao, Yijia, Xie, Yinping, Wei, Junyuan, Quan, Chengshi. 2022. CLDN6 inhibits breast cancer cell malignant behavior by suppressing ERK signaling. In Cellular signalling, 97, 110393. doi:10.1016/j.cellsig.2022.110393. https://pubmed.ncbi.nlm.nih.gov/35752352/

5. Dong, Yuan, Xu, Wenhong, Qi, Da, Wang, Xudong, Quan, Chengshi. 2023. CLDN6 inhibits colorectal cancer proliferation dependent on restraining p53 ubiquitination via ZO-1/PTEN axis. In Cellular signalling, 112, 110930. doi:10.1016/j.cellsig.2023.110930. https://pubmed.ncbi.nlm.nih.gov/37852424/

6. Yu, Site, Zhang, Yeqian, Li, Qing, Zhao, Gang, Xu, Jia. 2019. CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer. In Cell death & disease, 10, 949. doi:10.1038/s41419-019-2168-y. https://pubmed.ncbi.nlm.nih.gov/31827075/