MUC14 suppresses lung adenocarcinoma via integrin α8β6/PI3K/AKT/MAPK modulating cisplatin response and immunity

MUC14/Endomucin, a transmembrane mucin, is a potential prognostic biomarker in malignancies. This study aimed to elucidate the functional impact of MUC14 on tumor proliferation, migration, immune microenvironment modulation, and cisplatin response in lung adenocarcinoma (LUAD), and investigate its molecular mechanisms. LUAD cell lines with MUC14 overexpression (MUC14-OE) or silencing were constructed. Malignant behaviors were assessed via CCK-8, Transwell, and colony formation assays. Immune cell infiltration was quantified by CD3+/CD8 + immunohistochemistry. Subcutaneous xenograft and tail-vein metastasis murine models evaluated in vivo tumor progression and cisplatin responsiveness. Mechanisms were characterized using FRET and western blotting. Multiplatform bioinformatics analysis of public databases correlated MUC14 expression with clinical outcomes, immune infiltration, and chemotherapy response. MUC14-OE inhibited LUAD cell proliferation, migration, colony formation, and adhesion, while silencing promoted these phenotypes. MUC14 expression positively correlated with CD3+/CD8 + T-cell infiltration. In vivo, MUC14-OE suppressed subcutaneous tumor growth, lung metastasis, and enhanced cisplatin efficacy. Mechanistically, MUC14 inhibited integrin α8β6 clustering, suppressing PI3K/AKT and MAPK/ERK signaling. Cisplatin sensitization involved JNK/c-Jun pathway activation. This study establishes MUC14 as a multifunctional tumor suppressor in LUAD. It inhibits integrin α8β6-mediated PI3K/AKT and MAPK/ERK signaling to suppress tumor growth, promotes CD8+ T-cell infiltration, and augments cisplatin sensitivity via the JNK/c-Jun pathway. These findings nominate MUC14 as a prognostic biomarker and therapeutic target, suggesting combinatorial strategies integrating immunotherapy and chemotherapy.