NUF2 promotes the malignant development of lung adenocarcinoma through the mTORC1 signaling pathway via binding to...

Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality globally. Despite advances in therapy, treatment resistance and poor prognosis necessitate novel therapeutic targets. Nuclear filament-containing protein 2 (NUF2), a component of the nuclear division cycle 80 (NDC80) complex, is implicated in oncogenesis, but its role and molecular mechanisms in LUAD are poorly understood. The aim of this study is to explore the role of NUF2 in malignant development of LUAD in vivo.

Bioinformatics analysis using Gene Expression Profiling Interactive Analysis (GEPIA) and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases evaluated NUF2/BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B) expression and interactions. Functional assays (cell counting kit-8, colony formation, apoptosis, wound healing, transwell) and molecular techniques (real-time quantitative polymerase chain reaction, Western blot, co-immunoprecipitation) were performed in LUAD cell lines (A549, PC-9, NCI-H1975). The binding of NUF2 and BUB1B was verified by co-immunoprecipitation assay. An in vivo LUAD model was established with nude mice and the mTORC1 (mechanistic target of rapamycin complex 1) pathway was examined by Western blot.

NUF2 was significantly upregulated in LUAD tissues and correlated with advanced stage and poor survival (P<0.001). Silencing NUF2 suppressed proliferation, migration, and invasion while promoting apoptosis in A549 cells. Mechanistically, NUF2 directly bound to BUB1B, a mitotic checkpoint kinase, and regulated the mTORC1 pathway. Overexpression of BUB1B rescued the anti-tumor effects of NUF2 knockdown, restoring mTORC1 activity (evidenced by phosphorylation of 4EBP1 and S6). In vivo, NUF2 silencing inhibited tumor growth, which was reversed by BUB1B overexpression (P<0.01).

NUF2 drives LUAD progression via BUB1B-mediated mTORC1 activation. Targeting the NUF2/BUB1B axis may offer a promising therapeutic strategy to mitigate LUAD malignancy. These findings provide critical insights into the molecular underpinnings of LUAD and highlight potential pathways for clinical intervention.