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

Sep 23, 2026

Uploaded by Levi

MUC14/Endomucin is investigated as a multifunctional tumor suppressor and prognostic biomarker in lung adenocarcinoma (LUAD). MUC14 overexpression or silencing was introduced into LUAD cell lines, and proliferation, migration, adhesion, colony formation, immune infiltration, and in vivo tumor growth were evaluated. MUC14 enhanced CD3+/CD8+ T-cell infiltration and improved cisplatin efficacy in xenograft and metastasis models. Mechanistically, MUC14 disrupts integrin α8β6 clustering, suppressing PI3K/AKT and MAPK/ERK signaling, while cisplatin sensitization involves JNK/c-Jun pathway activation.

LanguageEnglish

CategoryHealthcare

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Pages17

Reading Time43 min

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Materials and methods

Cell lines

Cell transfection

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN MUC14 suppresses lung adenocarcinoma via integrin α8β6/ PI3K/AKT/MAPK modulating cisplatin response and immunity Xiaoqing Li1, Ming Li1, Shizhuan Huang2, Zhihua Zhang2, Chen Xing1, Shan Yu1,3􀀍 & Guiping Han1􀀍 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. Keywords Lung adenocarcinoma, MUC14, Integrin, Cisplatin, Immunotherapy Lung adenocarcinoma (LUAD) accounts for 40–55% of all lung cancer cases1. Despite recent advances in clinical management, the 5-year survival rate of LUAD patients remains below 20%, and 57–80% of patients eventually develop metastasis2. Cisplatin is still the standard first-line chemotherapeutic agent for advanced LUAD; however, its efficacy is severely limited by the development of drug resistance, which is primarily driven by aberrant DNA repair mechanisms, drug inactivation, and dysregulated apoptosis3,4. Thus, identifying novel therapeutic targets to overcome cisplatin resistance is of great clinical significance. The transmembrane mucin MUC14 (also known as EMCN) is defined by its extracellular O-glycosylation modifications and cytoplasmic phosphorylation motifs5,6. Previous studies have demonstrated that MUC14 overexpression promotes cell proliferation and metastasis in colon cancer7. However, its broader oncogenic functions across different cancer types remain incompletely characterized. Specifically, the role of MUC14 in lung cancer—especially its association with cisplatin response—has not been fully elucidated, except for one study showing that endothelial MUC14 deficiency facilitates LUAD metastasis8. Notably, MUC14 has been reported to regulate cell-matrix interactions, as it can disrupt integrin-mediated cell adhesion by impairing the formation of focal adhesion complexes in fibroblasts9. 1Department of Pathology, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China. 2Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China. 3Heilongjiang Mental Hospital, Harbin 150036, Heilongjiang, China. 􀀍 email: [yushan@hrbmu.edu.cn](yushan@hrbmu.edu.cn); [600400@hrbmu.ed

FAQs

What is the main role of MUC14 in LUAD cells?

MUC14 overexpression inhibits LUAD cell proliferation, migration, colony formation, and adhesion, while MUC14 silencing promotes these malignant phenotypes.

How does MUC14 affect immune infiltration and cisplatin efficacy?

MUC14 expression positively correlates with CD3+/CD8+ T-cell infiltration and suppresses subcutaneous tumor growth and lung metastasis, while enhancing cisplatin efficacy in vivo.

Which signaling pathways are linked to MUC14’s mechanism and cisplatin sensitization?

MUC14 inhibits integrin α8β6 clustering, suppressing PI3K/AKT and MAPK/ERK signaling. Cisplatin sensitization involves activation of the JNK/c-Jun pathway.

Sep 23, 2026

Uploaded by Levi