Year: 2026
Type: article
Abstract: BACKGROUND: NUF2 component of NDC80 kinetochore complex (NUF2) is a core regulatory protein that ensures proper chromosome segregation, and its aberrant expression is closely associated with cancer initiation and progression. Although the expression level of NUF2 is higher in non-small cell lung cancer (NSCLC) than in normal tissues, its mechanism of action in NSCLC remains unclear. This study aims to investigate the mechanism by which NUF2 promotes the proliferation, migration, and invasion of NSCLC. METHODS: The expression differences of NUF2 between NSCLC and normal lung tissues as well as the correlation between NUF2 expression and overall survival (OS) of NSCLC patients were analyzed via the Gene Expression Profiling Interactive Analysis (GEPIA) database. Immunohistochemical (IHC) staining was performed to detect the positive expression rate of NUF2 in NSCLC specimens. NUF2 knockdown and overexpression stable cell lines were established in the A549 cell line, and transfection efficiency was verified by Western blot (WB) and quantitative real-time polymerase chain reaction (RT-qPCR). The proliferation, migration, and invasion of transfected cells were assessed using the cell counting kit-8 (CCK-8), colony formation assay, wound healing assay, and Transwell assay. The expression levels of ferroptosis-related proteins were determined using WB and RT-qPCR. Commercial assay kits were utilized to measure the contents of malondialdehyde (MDA), reactive oxygen species (ROS), ferrous ion (Fe²+) and glutathione (GSH), while intracellular mitochondrial structural alterations were visualized by transmission electron microscopy (TEM). Xenograft tumor models were established. The expression levels of NUF2, SLC7A11 and ACSL4 were detected by WB, RT‑qPCR and IHC. RESULTS: GEPIA analysis revealed that NUF2 was significantly highly expressed in NSCLC (P<0.05) and was associated with OS (P<0.001). Clinical statistical analyses demonstrated that upregulated NUF2 was significantly associated with advanced clinical stage (P<0.05) and lymph node metastasis (P<0.01). NUF2 knockdown markedly suppressed the proliferation, migration and invasion of NSCLC cells (P<0.001) and reduced xenograft tumor volume in vivo (P<0.05). Mechanistically, NUF2 silencing downregulated the expression of the ferroptosis master regulator SLC7A11 (P<0.01) while upregulating ACSL4 (P<0.01). The levels of MDA (P<0.01), ROS and Fe²+ (P<0.001) were all elevated following NUF2 knockdown, while the content of GSH decreased (P<0.001). TEM observation revealed that NUF2 knockdown led to mitochondrial shrinkage, reduced cristae number and increased membrane density. Conversely, NUF2 overexpression enhanced NSCLC cell proliferation, migration and invasion (P<0.001) and increased xenograft tumor volume (P<0.001). Meanwhile, SLC7A11 expression was elevated (P<0.01) and ACSL4 expression was decreased (P<0.01). The levels of ROS (P<0.001), MDA and Fe²+ were decreased (P<0.01), and the GSH level was increased (P<0.01). CONCLUSIONS: NUF2 is highly expressed in NSCLC and is closely associated with poor prognosis and lymph node metastasis. NUF2 inhibits ferroptosis by upregulating SLC7A11 expression and downregulating ACSL4 expression, thereby promoting the proliferation, migration, and invasion of NSCLC.
Source: PubMed Central
Language: Chinese
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223028625