Through the PI3K/AKT and ERK pathways, NETO2 stimulates proliferation and metastasis, which advances the course of esophageal cancer

Abstract

About 90% of esophageal cancer cases are esophageal squamous cell carcinomas (ESCC), which are
aggressive, deadly cancers with very poor prognoses. Genes that code for the proteins neuropilin and tolloid
like 2 (NETO2) have been linked to a number of human malignancies. However, not much is known
regarding the clinical importance of the phenotypic manifestation in the course of ESCC. According to our
research, the clinical stage of the tumor and the presence of lymph node metastases were related to NETO2
expression in ESCC patients. NETO2 suppressed apoptosis in vitro and promoted tumor development in vivo,
while stimulating ESCC cell proliferation, according to gain-of-function and loss-of-function investigations.
Furthermore, in conjunction with the control of markers associated with the epithelial-mesenchymal
transition (EMT), NETO2 knockdown markedly reduced migration and invasion. Mechanistically, ERK,
PI3k/AKT, and nuclear factor erythroid-2-related factor 2 (Nrf2) were all more phosphorylated when NETO2
was overexpressed, but these targets were less phosphorylated when NETO2 was silenced. According to our
findings, Nrf2 is a key downstream event that initiates the PI3K/AKT and ERK signaling pathways and is
essential for NETO2-mediated carcinogenesis. When combined, NETO2 functions as an oncogene and may
be a new therapeutic target or prognostic biomarker for patients with ESCC.