NETO2, or Neuropilin and tolloid-like 2, is a protein-coding gene. It acts as an auxiliary subunit of kainate receptors in the central nervous system, regulating their trafficking, gating kinetics, and pharmacology [2,3,6]. It is also involved in multiple signaling pathways such as PI3K/AKT, ERK, and Ca2+/CaMKII, which are crucial for various biological processes [1,4]. Dysregulation of NETO2 has been associated with the progression of several cancers, making it potentially important for understanding tumorigenesis [1,4,5,7,8,9].

In esophageal squamous cell carcinoma (ESCC), gain-and loss-of-function analyses showed that NETO2 promotes cell proliferation, suppresses apoptosis, and enhances tumor growth in vivo, while knockdown inhibits migration, invasion, and regulates epithelial-mesenchymal transition (EMT) related markers via the PI3K/AKT and ERK pathways [1]. In melanoma, disrupting NETO2 expression inhibits proliferation, growth, migration, and invasion by downregulating calcium-related factors [4]. In osteosarcoma, NETO2 depletion represses cell malignancy and triggers apoptosis, and it is negatively regulated by miR-101-3p [5]. In gastric cancer, NETO2 overexpression promotes migration, invasion, and metastasis, while knockdown has the opposite effects, with the PI3K/Akt/NF-κB/Snail axis involved [7]. In pancreatic cancer, knockdown of NETO2 arrests the cell cycle and inhibits multiple tumor-related cellular functions, and the STAT3 signaling pathway is involved [9].

In conclusion, NETO2 plays essential roles in both normal neuronal function through its modulation of kainate receptors and in disease, particularly in the progression of various cancers. Loss-of-function experiments in these cancer models have revealed its oncogenic properties, highlighting its potential as a therapeutic target or prognostic biomarker in cancer treatment [1,4,5,7,9].