Abstract
Background
Lung cancer is a common malignant tumor with high morbidity and mortality rate. GNPNAT1 has been identified as a metastasis-associated gene in LUAD. However, the exact role and related mechanism of GNPNAT1 in regulating LUAD metastasis remain largely unknown.
Method
We analyzed the expression of GNPNAT1 in the TIMER2, GEPIA2 and GEO databases and confirmed the results by immunohistochemistry (IHC). The potential biological functions of GNPNAT1 in LUAD was investigated based on TCGA-LUAD database. The correlations between GNPNAT1 and cancer immune characteristics were analyzed via the ESTIMATE and CIBERSORT R package. The underlying mechanisms of altered GNPNAT1 expression on LUAD cell tumorigenesis, proliferation, migration, invasion, and metastasis were explored in vitro and in vivo.
Result
We demonstrated that GNPNAT1 expression was markedly increased in lung adenocarcinoma (LUAD) tissues and negatively correlated with the overall survival (OS) of patients. hsa − miR − 1−3p and hsa − miR − 26a − 5p were the upstream miRNA targets of GNPNAT1. GNPNAT1 was positively correlated with the infiltration levels of CD8 T cells, memory activated CD4 T cells, NK cells resting, Macrophages M0, Macrophages M1, Neutrophils, gamma delta T cells, Eosinophils, and was negatively correlated with memory resting CD4 T cells, regulatory T cells (Tregs), resting NK cells, Monocytes, resting dendritic cells, resting mast cells. GNPNAT1 knockdown significantly inhibited proliferation, migration, invasion, EMT, and metastasis of LUAD cell, while overexpression of GNPNAT1 revealed the opposite effects. Rescue assay showed that Slug knockdown reversed GNPNAT1-induced LUAD cells migration, invasion, and EMT. Mechanistically, GNPNAT1 promoted cancer cells metastasis via repressing ubiquitination degradation of Slug in LUAD.
Conclusion
These data indicated that GNPNAT1 was critical for proliferation, migration, invasion, EMT process, and metastasis of LUAD cells and may be a potential therapeutic target for LUAD.