NETO2, short for Neuropilin and tolloid-like 2, is a gene that encodes a protein acting as an accessory subunit of kainate receptors, predominantly expressed in the brain. It has been associated with regulating the trafficking, gating kinetics, and pharmacology of kainate receptors [2,3,6]. In addition, it is involved in multiple signaling pathways such as PI3K/AKT, ERK, Ca2+/CaMKII, and is of great importance in various biological processes and diseases [1,4]. Genetic models, like the use of Nothobranchius furzeri to study neto2b ortholog, can help in understanding its functions [7].

In cancer research, loss-of-function analyses in various cancer cell lines have shown significant effects of NETO2. In esophageal squamous cell carcinoma (ESCC), knockdown of NETO2 inhibited cell proliferation, migration, and invasion, and regulated epithelial-mesenchymal transition (EMT) related markers. It was found to act through the PI3K/AKT and ERK pathways, with Nrf2 being a critical downstream event [1]. Similar effects were seen in melanoma, osteosarcoma, gastric cancer, and pancreatic cancer. In melanoma, disrupting NETO2 expression inhibited proliferation, migration, and invasion by down-regulating calcium-related signaling [4]. In osteosarcoma, NETO2 depletion repressed cell malignancy [5]. In gastric cancer, knockdown of NETO2 reduced the phosphorylation of PI3K, AKT, and NF-κB p65, inhibiting invasion and metastasis [8]. In pancreatic cancer, NETO2 knockdown arrested the cell cycle and inhibited multiple malignant phenotypes [9].

In conclusion, NETO2 plays essential roles in regulating kainate receptor functions. Model-based research, especially loss-of-function experiments in cancer cell lines, has revealed its significant role in promoting cancer progression in various types of cancer, including ESCC, melanoma, osteosarcoma, gastric cancer, and pancreatic cancer. Understanding NETO2 can potentially offer new therapeutic targets for these diseases.

References:

1. Xu, Jia-Cheng, Chen, Tian-Yin, Liao, Le-Tai, Zhou, Ping-Hong, Zhang, Yi-Qun. 2021. NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway. In International journal of biological sciences, 17, 259-270. doi:10.7150/ijbs.53795. https://pubmed.ncbi.nlm.nih.gov/33390848/

2. He, Lingli, Sun, Jiahui, Gao, Yiwei, Shi, Yun Stone, Zhao, Yan. 2021. Kainate receptor modulation by NETO2. In Nature, 599, 325-329. doi:10.1038/s41586-021-03936-y. https://pubmed.ncbi.nlm.nih.gov/34552241/

3. Han, Liwei, Howe, James R, Pickering, Darryl S. 2016. Neto2 Influences on Kainate Receptor Pharmacology and Function. In Basic & clinical pharmacology & toxicology, 119, 141-8. doi:10.1111/bcpt.12575. https://pubmed.ncbi.nlm.nih.gov/26928870/

4. Zhu, Susi, Zhang, Xu, Guo, Yeye, Chen, Xiang, Peng, Cong. 2023. NETO2 promotes melanoma progression via activation of the Ca2+/CaMKII signaling pathway. In Frontiers of medicine, 17, 263-274. doi:10.1007/s11684-022-0935-0. https://pubmed.ncbi.nlm.nih.gov/36738427/

5. Zhang, Zun, Wang, Jin, Zhang, Xiaoyan, Wen, Jie, Zhang, Hong. 2022. TYMSOS-miR-101-3p-NETO2 axis promotes osteosarcoma progression. In Molecular and cellular probes, 67, 101887. doi:10.1016/j.mcp.2022.101887. https://pubmed.ncbi.nlm.nih.gov/36509232/

6. Tomita, Susumu, Castillo, Pablo E. 2012. Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors. In The Journal of physiology, 590, 2217-23. doi:10.1113/jphysiol.2011.221101. https://pubmed.ncbi.nlm.nih.gov/22431337/

7. Fedorova, Maria S, Snezhkina, Anastasiya V, Lipatova, Anastasiya V, Krasnov, George S, Kudryavtseva, Anna V. 2020. NETO2 Is Deregulated in Breast, Prostate, and Colorectal Cancer and Participates in Cellular Signaling. In Frontiers in genetics, 11, 594933. doi:10.3389/fgene.2020.594933. https://pubmed.ncbi.nlm.nih.gov/33362854/

8. Liu, Jun-Yan, Jiang, Lei, He, Tao, Cui, You-Hong, Yu, Pei-Wu. 2019. NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients. In Cell death & disease, 10, 162. doi:10.1038/s41419-019-1388-5. https://pubmed.ncbi.nlm.nih.gov/30770791/

9. Li, Yaxiong, Zhang, Yongping, Liu, Jiansheng. 2019. NETO2 promotes pancreatic cancer cell proliferation, invasion and migration via activation of the STAT3 signaling pathway. In Cancer management and research, 11, 5147-5156. doi:10.2147/CMAR.S204260. https://pubmed.ncbi.nlm.nih.gov/31239769/