DSG2 attenuates gemcitabine efficacy through PTX3 in lung adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, often diagnosed at an advanced stage with poor prognosis and limited treatment options. The Desmoglein (DSG) family plays a crucial role in maintaining cell adhesion and tissue integrity. Upregulation of DSG proteins has been implicated in tumorigenesis, invasion, and metastasis across various cancers. However, the role of DSG in lung cancer, particularly as a biomarker influencing the efficacy of anti-cancer drugs, remains unclear. In this study, DSG2 was significantly overexpressed in LUAD tumor tissues and correlated with poor prognosis, as revealed by TCGA database analysis. Additionally, analyses of single-cell sequencing, KEGG, and GSEA multi-omics databases demonstrated that DSG2 modulates multiple oncogenic pathways, particularly the apoptosis pathway, with a strong positive correlation between DSG2 and PTX3 expression. In vitro experiments showed that DSG2 knockdown enhanced gemcitabine-induced apoptosis by downregulating the NFκB/STAT3/PTX3 signaling axis. Furthermore, adding recombinant PTX3 protein in DSG2 knockdown cells restored STAT3 activation, reducing gemcitabine efficacy, indicating that DSG2 contributes to gemcitabine resistance through PTX3-mediated mechanisms. This study identifies DSG2 as a critical mediator of gemcitabine resistance in LUAD through its regulation of the PTX3/NFκB/STAT3 pathway. The findings suggest that targeting DSG2 could enhance the therapeutic efficacy of gemcitabine in LUAD patients, offering a novel therapeutic strategy and biomarker for overcoming chemoresistance in this aggressive cancer subtype.