DSG2 attenuates gemcitabine efficacy through PTX3 in lung adenocarcinoma

Chin-Chou Wang; Jo-Ying Lin; Chih-Yang Wang; Wan-Jou Shen; Pin-Chen Liao; Yu-Fang Ho; Che-Wei Lin; Shao-An Wang; Ching-Chung Ko; Sanskriti Dey; Hoang Dang Khoa Ta; Do Thi Minh Xuan; Sachin Kumar; Bianca Tobias William; Ju-Ming Wang; Wei-Jan Wang

doi:10.1016/j.bbadis.2025.167881

DSG2 attenuates gemcitabine efficacy through PTX3 in lung adenocarcinoma

Biochim Biophys Acta Mol Basis Dis. 2025 Aug;1871(6):167881. doi: 10.1016/j.bbadis.2025.167881. Epub 2025 Apr 30.

Authors

Affiliations

¹ Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
² Department of Biological Science and Technology, China Medical University, Taichung 40676, Taiwan.
³ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.
⁵ Department of Medical Imaging, Chi-Mei Medical Center, Tainan, Taiwan; Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁶ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁷ Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
⁸ Faculty of Pharmacy, Van Lang University, 69/68 Dang Thuy Tram Street, Ward 13, Binh Thanh District, Ho Chi Minh City 70000, Viet Nam.
⁹ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Faculty of Biotechnology and Applied Sciences, Shoolini University of Biotechnology and Management Sciences, Himachal Pradesh, India.
¹⁰ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Department of Biomedicine, School of Life Sciences, Indonesia International Institute for Life Sciences, Jl Pulomas Barat Kav 88, Jakarta Timur 13210, Indonesia.
¹¹ Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹² Department of Biological Science and Technology, China Medical University, Taichung 40676, Taiwan; Cancer Biology and Precision Therapeutics Center and Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan. Electronic address: cvcsky@cmu.edu.tw.

PMID: 40316058
DOI: 10.1016/j.bbadis.2025.167881

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.

Keywords: DSG2; Gemcitabine resistance; Lung adenocarcinoma; NFκB; PTX3.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / metabolism
Adenocarcinoma of Lung* / pathology
Apoptosis / drug effects
C-Reactive Protein
Cell Line, Tumor
Deoxycytidine* / analogs & derivatives
Deoxycytidine* / pharmacology
Deoxycytidine* / therapeutic use
Desmoglein 2* / genetics
Desmoglein 2* / metabolism
Drug Resistance, Neoplasm / genetics
Female
Gemcitabine
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Male
NF-kappa B / metabolism
Pentraxins
Prognosis
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Serum Amyloid P-Component* / genetics
Serum Amyloid P-Component* / metabolism
Signal Transduction / drug effects

Substances

Deoxycytidine
Gemcitabine
Desmoglein 2
Serum Amyloid P-Component
STAT3 Transcription Factor
NF-kappa B
C-Reactive Protein
Pentraxins
DSG2 protein, human
STAT3 protein, human