CNTN5 Promotes Invasion and Metastasis in Non-Small Cell Lung Cancer by Regulating YAP1 Nuclear Translocation.

BACKGROUND

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide, largely owing to its high metastatic potential. Contactin-5 (CNTN5), a glycosylphosphatidylinositol-anchored membrane protein, has been implicated in tumor-related processes; however, its role in NSCLC progression remains unclear. This study aimed to investigate the clinical relevance, biological function, and underlying mechanism of CNTN5 in NSCLC.

METHODS

CNTN5 expression was evaluated using public databases and clinical NSCLC specimens. Gain- and loss-of-function assays were performed in NSCLC cell lines. Cell proliferation, migration, and invasion were assessed using CCK-8, wound healing, and Transwell assays, respectively. An experimental lung metastasis model was used to determine metastatic capacity in vivo. RNA sequencing and enrichment analysis were performed to explore the molecular mechanisms involved.

RESULTS

CNTN5 was upregulated in NSCLC tissues and was associated with poor prognosis. CNTN5 overexpression significantly enhanced NSCLC cell migration and invasion, while increased CNTN5 expression promoted lung metastatic colonization in vivo. Transcriptomic and protein analyses indicated that CNTN5 was associated with alterations in Hippo signaling pathway. In addition, CNTN5 increased YAP1 expression and promoted its nuclear translocation, while YAP1 silencing partially reversed the pro-migratory and pro-invasive effects induced by CNTN5. Co-immunoprecipitation analyses further supported an interaction between CNTN5 and PTPN13, accompanied by enhanced nuclear localization of YAP1.

CONCLUSIONS

CNTN5 promotes NSCLC progression, particularly invasion and metastasis, and is associated with unfavorable clinical outcomes. Mechanistically, CNTN5 enhances YAP1 nuclear translocation and activates YAP1-associated transcriptional programs, highlighting its potential as a prognostic biomarker and therapeutic target in NSCLC.