NPM3 as a novel oncogenic factor and poor prognostic marker contributes to cell proliferation and migration in lung adenocarcinoma

Abstract

Background Lung cancer is the leading cause of cancer-related deaths worldwide, and despite recent advances in targeted therapies and immunotherapies, the clinical benefit remains limited. Therefore, there is an urgent need to further investigate the molecular mechanisms underlying lung cancer. The aim of this study was to investigate the expression and function of NPM3 in the tumor microenvironment of lung adenocarcinoma (LUAD). Methods We utilized bioinformatics tools and databases, including UALCAN, GEPIA2, HPA, and Sangerbox, to analyze NPM3 expression in LUAD samples and its association with prognosis and mutational landscape. NPM3 expression in various cell types was assessed at the single cell level using the TISCH database. We also used algorithms such as TIMER and EPIC to explore the crosstalk between NPM3 expression and immune features. KEGG enrichment analysis was performed to identify potential signaling pathways of NPM3. Finally, we employed siRNA knockdown strategy to investigate the effect of NPM3 on LUAD cell proliferation and migration in vitro. Results NPM3 was significantly upregulated in LUAD tissues and was strongly associated with poor prognosis and TP53 gene mutations. Single-cell sequencing analysis revealed that NPM3 was expressed in immune cells (dendritic cells and monocytes/macrophages) in the tumor microenvironment. Moreover, NPM3 expression was negatively associated with immune B cell and CD4 T cell infiltration, as well as with several immune-related genes (including CCL22, CXCR2, CX3CR1, CCR6, HLA-DOA, HLA-DQA2). KEGG enrichment analysis indicated that NPM3 expression was associated with cell cycle, CAMs, and NSCLC pathway genes. Finally, in vitro experiments showed that NPM3 knockdown inhibited LUAD cell proliferation and migration in NCI-H1299 and SPC-A1 cells, and suppressed the expression of CCNA2 and MAD2L1. Conclusion Elevated NPM3 expression predicts poor clinical outcome and an immunosuppressive microenvironment in LUAD tissues. NPM3 promotes LUAD progression by promoting cell proliferation and migration, and targeting NPM3 may represent a novel therapeutic strategy for LUAD. Graphical Abstract

SET7/9-mediated methylation affects oncogenic functions of histone demethylase JMJD2A

“…To our knowledge, this is the first time that NPM3 has been shown to stimulate tumorigenesis in vivo and, therefore, the present study uncovered NPM3 as a potential oncoprotein. While this study was under revision, another report demonstrated that NPM3 can stimulate proliferation and migration of lung adenocarcinoma cells in vitro ( 46 ). Accordingly, NPM3 inhibitors might be useful for prostate and lung cancer therapy.…”

Characterization of the AGR2-NPM3 axis uncovers the AGR2 involvement in PD-L1 regulation in colorectal cancer

“…Nucleoplasmin-3 (NPM3), which we identi ed as a protein with a similar expression pattern to AGR2 in CRC, is an emerging oncoprotein primarily localised in the nucleus and nucleolus, where it exerts its function in ribosome biogenesis by regulating pre-rRNA synthesis and chromatin remodelling function when bound in a pentameric conformation with NPM1 [10,11]. In lung adenocarcinoma, NPM3 is positively correlated with proliferation, while in gastric cancer, it promotes PD-L1-mediated immune escape [12,13].…”