PCDH9, a member of the protocadherin superfamily, is involved in cell-cell interactions. In the nervous system, it may play a role in synaptogenesis and the regulation of synaptic function. In the context of cancer, it has been implicated in tumor-suppressing pathways, with potential impacts on cell proliferation, apoptosis, and migration [1-10]. Genetic models, such as gene knockout mouse models, can be valuable for further elucidating its functions.

In melanoma, interference and overexpression studies using lentivirus showed that PCDH9 negatively correlates with MMP2, MMP9, and RAC1, and positively with CCND1 and apoptosis. Overexpressed PCDH9 suppresses melanoma cell proliferation and migration [1]. In hepatocellular carcinoma, methylation of the PCDH9 promoter was observed in some tissues, and restored PCDH9 expression inhibited tumor cell proliferation via cell cycle arrest at G0/G1 phase [2]. In glioma, miR-215-5p up-regulation dual-inhibits PCDH9 expression, and restored PCDH9 expression reduces tumor cell viability, induces apoptosis, and suppresses invasion [3,6]. In gastric cancer, cleaved PCDH9 translocates to the nucleus, down-regulating CDH2 expression and impairing metastasis [4]. In the mouse hippocampus, Pcdh9 KO neurons exhibit synapse overgrowth, transcriptional alterations, and defective network activity [5].

In conclusion, PCDH9 has important functions in both normal biological processes like synaptogenesis and in disease conditions, particularly cancer. Model-based research, especially gene knockout mouse models, has revealed its role in suppressing tumor cell growth, invasion, and metastasis in various cancers, and in regulating synaptic morphology and function in the nervous system.

References:

1. Zhang, Jiaojiao, Yang, Hui-Zhi, Liu, Shuang, Wang, Zuhua, Chen, RongYi. 2022. PCDH9 suppresses melanoma proliferation and cell migration. In Frontiers in oncology, 12, 903554. doi:10.3389/fonc.2022.903554. https://pubmed.ncbi.nlm.nih.gov/36452505/

2. Lv, Jun, Zhu, Pengfei, Zhang, Xiaolei, Yu, Zujiang, Liu, Shuang. 2017. PCDH9 acts as a tumor suppressor inducing tumor cell arrest at G0/G1 phase and is frequently methylated in hepatocellular carcinoma. In Molecular medicine reports, 16, 4475-4482. doi:10.3892/mmr.2017.7193. https://pubmed.ncbi.nlm.nih.gov/28791409/

3. Wang, Chunlin, Chen, Qi, Li, Shu, Tao, Bangbao, Zhong, Jun. . Dual inhibition of PCDH9 expression by miR-215-5p up-regulation in gliomas. In Oncotarget, 8, 10287-10297. doi:10.18632/oncotarget.14396. https://pubmed.ncbi.nlm.nih.gov/28055966/

4. Zhang, Yajuan, Zhu, Yingwei, Chen, Ying, Yang, Weiwei, Yu, Guanzhen. 2024. Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression. In iScience, 27, 109011. doi:10.1016/j.isci.2024.109011. https://pubmed.ncbi.nlm.nih.gov/38357662/

5. Miozzo, Federico, Murru, Luca, Maiellano, Greta, Moretto, Edoardo, Passafaro, Maria. 2024. Disruption of the autism-associated Pcdh9 gene leads to transcriptional alterations, synapse overgrowth, and defective network activity in the CA1. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 44, . doi:10.1523/JNEUROSCI.0491-24.2024. https://pubmed.ncbi.nlm.nih.gov/39557582/

6. Wang, Chunlin, Tao, Bangbao, Li, Shiting, Lu, Yicheng, Liu, Jiachuan. 2013. Characterizing the role of PCDH9 in the regulation of glioma cell apoptosis and invasion. In Journal of molecular neuroscience : MN, 52, 250-60. doi:10.1007/s12031-013-0133-2. https://pubmed.ncbi.nlm.nih.gov/24214103/