CXCL12 is a potential therapeutic target for type 2 diabetes mellitus complicated by chronic obstructive pulmonary disease

doi:10.12122/j.issn.1673-4254.2025.01.13

Abstract

Abstract:

Objective To identify the key genes and immunological pathways shared by type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) and explore the potential therapeutic targets of T2DM complicated by COPD. Methods GEO database was used for analyzing the gene expression profiles in T2DM and COPD to identify the common differentially expressed genes (DEGs) in the two diseases. A protein-protein interaction network was constructed to identify the candidate hub genes, which were validated in datasets and disease sets to obtain the target genes. The diagnostic accuracy of these target genes was assessed with ROC analysis, and their expression levels and association with pulmonary functions were investigated using clinical data and blood samples of patients with T2DM and COPD. The abundance of 22 immune cells was analyzed with CIBERSORT algorithm, and their relationship with the target genes was examined using correlation analysis. DGIdb database was used for analyzing the drug-gene interactions and the druggable genes followed by gene set enrichment analysis. Results We identified a total of 175 common DEGs in T2DM and COPD, mainly enriched in immune- and inflammation-related pathways. Among these genes, CXCL12 was identified as the final target gene, whose expression was elevated in both T2DM and COPD (P<0.05) and showed good diagnostic efficacy. Immune cell infiltration correlation analysis showed significant correlations of CXCL12 with various immune cells (P<0.01). GESA analysis showed that high CXCL12 expression was significantly correlated with "cytokine-cytokine receptor interaction". Drug-gene analysis showed that most of CXCL12-related drugs were not targeted drugs with significant cytotoxicity. Conclusion CXCL12 is a potential common key pathogenic gene of COPD and T2DM, and small-molecule targeted drugs against CXCL12 can provide a new strategy for treatment T2DM complicated by COPD.

Key words: type 2 diabetes mellitus, chronic obstructive pulmonary disease, bioinformatics analysis, CXCL12, drug target analysis

Huaiwen XU, Li WENG, Hong XUE. CXCL12 is a potential therapeutic target for type 2 diabetes mellitus complicated by chronic obstructive pulmonary disease[J]. Journal of Southern Medical University, 2025, 45(1): 100-109.

Figures/Tables 8

Tab.1 Information of the datasets used in this study

Database	Molecule	Tissue	Subgroup	Number	Platform
GSE76925	mRNA	Lung tissue samples	COPD Non-COPD	111 40	GPL10558
GSE76894	mRNA	Islet samples	T2DM Non-diabetic	19 84	GPL570
GSE37768	mRNA	Lung tissue samples	COPD Non-COPD	20 18	GPL570
GSE25724	mRNA	islet samples	T2DM Non-diabetic	7 7	GPL96

Fig.1 Screening of the common differentially expressed genes in COPD and T2DM. A: Volcano plots of gene expression changes in GSE76925. B: Volcano plots of gene expression changes in GSE76894. C: Venn diagrams of the intersected DEGs.

Fig.2 Functional enrichment analyses of the common differentially expressed genes in COPD and T2DM using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A: KEGG analysis of the upregulated genes. B: KEGG analysis of the downregulated genes. C: GO analysis of the upregulated genes. D: GO analysis of the downregulated genes.

Fig.3 Protein-protein interaction network and identification of the candidate hub genes. A: PPI network diagram (Red: Upregulated genes; Green: downregulated genes). B: The top20 core gene networks predicted and explored using 4 topology algorithms. C: Venn diagram of the core genes identified by the 4 topology algorithms. D: Friend analysis of 10 common genes.

Fig.4 Validation of the candidate hub genes and evaluation of their diagnostic effectiveness. A: Hub-gene expression in the analyzing datasets. B: Hub-gene expression in the validating datasets. C: Hub-gene ROC curves and AUC statistics in the analyzing datasets and validating datasets. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

Fig.5 Validation of CXCL12 expressions in clinical blood samples. A: Elevated CXCL12 in patients with T2DM complicated by COPD (n=12,*P<0.05). B: Correlation between CXCL12 and FEV1pred% in patients with T2DM complicated by COPD (n=20).

Fig.6 Correlation analysis of the candidate hub genes and immune cells in COPD and T2DM. A: Violin plot of the distribution of immune cells in GSE76925. B: Violin plot of the distribution of immune cells in GSE76894. C: Heat map of the hub genes and immune infiltration in GSE76925. D: Heat map of the hub genes and immune infiltration in GSE76894. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

Fig.7 Drug-gene analysis (A) and GSEA enrichment analysis of CXCL12 gene expression (B).

References 35

1	Agustí A, Celli BR, Criner GJ, et al. Global initiative for chronic obstructive lung disease 2023 report: gold executive summary[J]. Am J Respir Crit Care Med, 2023, 207(7): 819-37.
2	Rana JS, Khan SS, Lloyd-Jones DM, et al. Changes in mortality in top 10 causes of death from 2011 to 2018[J]. J Gen Intern Med, 2021, 36(8): 2517-8.
3	López-Campos JL, Tan W, Soriano JB. Global burden of COPD[J]. Respirology, 2016, 21(1): 14-23.
4	Castañ-Abad MT, Montserrat-Capdevila J, Godoy P, et al. Diabetes as a risk factor for severe exacerbation and death in patients with COPD: a prospective cohort study[J]. Eur J Public Health, 2020, 30(4): 822-7.
5	Stolz D, Mkorombindo T, Schumann DM, et al. Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission[J]. Lancet, 2022, 400(10356): 921-72.
6	Gayle A, Dickinson S, Poole C, et al. Incidence of type II diabetes in chronic obstructive pulmonary disease: a nested case-control study[J]. NPJ Prim Care Respir Med, 2019, 29(1): 28.
7	Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets: update[J]. Nucleic Acids Res, 2013, 41(Database issue): D991-5.
8	Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies[J]. Nucleic Acids Res, 2015, 43(7): e47.
9	Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis[J]. BMC Bioinformatics, 2008, 9: 559.
10	Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets[J]. Nucleic Acids Res, 2021, 49(D1): D605-12.
11	Chin CH, Chen SH, Wu HH, et al. cytoHubba: identifying hub objects and sub-networks from complex interactome[J]. BMC Syst Biol, 2014, 8(): S11.
12	Yu GC, Li F, Qin YD, et al. GOSemSim: an R package for measuring semantic similarity among GO terms and gene products[J]. Bioinformatics, 2010, 26(7): 976-8.
13	Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves[J]. BMC Bioinformatics, 2011, 12: 77.
14	Chen BB, Khodadoust MS, Liu CL, et al. Profiling tumor infiltrating immune cells with CIBERSORT[J]. Methods Mol Biol, 2018, 1711: 243-59.
15	Cotto KC, Wagner AH, Feng YY, et al. DGIdb 3.0: a redesign and expansion of the drug-gene interaction database[J]. Nucleic Acids Res, 2018, 46(D1): D1068-73.
16	Katsiki N, Steiropoulos P, Papanas N, et al. Diabetes mellitus and chronic obstructive pulmonary disease: an overview[J]. and, 2021, 129(10): 699-704.
17	Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD[J]. Eur Respir J, 2008, 32(4): 962-9.
18	Dupin I, Thumerel M, Maurat E, et al. Fibrocyte accumulation in the airway walls of COPD patients[J]. Eur Respir J, 2019, 54(3): 1802173.
19	Murdoch C, Thornhill MH, Fang HY, et al. CXCL12/CXCR4 axis mediates recruitment of monocytes to oral cancer spheroids [J]. Oral Dis, 2012, 18(6): 8-18.
20	Elena T, James O, Ann H, et al. Caveolin-1 regulates CXCR4/CXCL12-dependent monocyte recruitment in scleroderma patients and in a murine model of interstitial lung disease[J]. Clin Experim Rheumatol, 2010, 28(5): S79-80.
21	Hao WD, Li MX, Pang YM, et al. Increased chemokines levels in patients with chronic obstructive pulmonary disease: correlation with quantitative computed tomography metrics[J]. Br J Radiol, 2021, 94(1118): 20201030.
22	Aydin Ozgur B, Coskunpinar E, Bilgic Gazioglu S, et al. Effects of complement regulators and chemokine receptors in type 2 diabetes[J]. Immunol Invest, 2021, 50(5): 478-91.
23	Alagpulinsa DA, Cao JJL, Sobell D, et al. Harnessing CXCL12 signaling to protect and preserve functional β-cell mass and for cell replacement in type 1 diabetes[J]. Pharmacol Ther, 2019, 193: 63-74.
24	Yin QZ, Sun KX, Xiang X, et al. Identification of novel CXCL12 genetic polymorphisms associated with type 2 diabetes mellitus: a Chinese sib-pair study[J]. Genet Test Mol Biomarkers, 2019, 23(7): 435-41.
25	Gredic M, Sharma V, Hadzic S, et al. iNOS deletion in alveolar epithelium cannot reverse the elastase-induced emphysema in mice[J]. Cells, 2022, 12(1): 125.
26	Choy JC, Yi T, Rao DA, et al. CXCL12 induction of inducible nitric oxide synthase in human CD8 T cells[J]. J Heart Lung Transplant, 2008, 27(12): 1333-9.
27	Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer[J]. Clin Cancer Res, 2010, 16(11): 2927-31.
28	Pallett LJ, Swadling L, Diniz M, et al. Tissue CD14⁺CD8⁺ T cells reprogrammed by myeloid cells and modulated by LPS[J]. Nature, 2023, 614(7947): 334-42.
29	Lim K, Hyun YM, Lambert-Emo K, et al. Neutrophil trails guide influenza-specific CD8⁺ T cells in the airways[J]. Science, 2015, 349(6252): aaa4352.
30	Zhong T, Li XY, Lei K, et al. CXCL12-CXCR4 mediates CD57⁺ CD8⁺ T cell responses in the progression of type 1 diabetes[J]. J Autoimmun, 2024, 143: 103171.
31	Barwinska D, Oueini H, Poirier C, et al. AMD3100 ameliorates cigarette smoke-induced emphysema-like manifestations in mice[J]. Am J Physiol Lung Cell Mol Physiol, 2018, 315(3): L382-6.
32	Cazzola M, Rogliani P, Ora J, et al. Hyperglycaemia and chronic obstructive pulmonary disease[J]. Diagnostics, 2023, 13(21): 3362.
33	Au PCM, Tan KCB, Lam DCL, et al. Association of sodium-glucose cotransporter 2 inhibitor vs dipeptidyl peptidase-4 inhibitor use with risk of incident obstructive airway disease and exacerbation events among patients with type 2 diabetes in Hong Kong [J]. JAMA Netw Open, 2023, 6(1): e2251177.
34	Pradhan R, Lu S, Yin H, et al. Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study[J]. BMJ, 2022, 379: e071380.
35	Janssens R, Struyf S, Proost P. The unique structural and functional features of CXCL12[J]. Cell Mol Immunol, 2018, 15(4): 299-311.

[1]	Hongli YANG, Yayun XIANG, Tingting TAN, Yang LEI. ORY-1001 inhibits glioblastoma cell growth by downregulating the Notch/HES1 pathway via suppressing lysine-specific demethylase 1 expression [J]. Journal of Southern Medical University, 2024, 44(8): 1620-1630.
[2]	LIANG Yihao, LAI Yingjun, YUAN Yanwen, YUAN Wei, ZHANG Xibo, ZHANG Bashan, LU Zhifeng. Screening of differentially expressed genes in gastric cancer based on GEO database and function and pathway enrichment analysis [J]. Journal of Southern Medical University, 2024, 44(3): 605-616.
[3]	Zijing REN, Peiyang ZHOU, Jing TIAN. Plasma long noncoding RNA expression profiles in patients with Parkinson's disease and the role of lnc-CTSD-5:1 in a PD cell model: a ceRNA microarray-based study [J]. Journal of Southern Medical University, 2024, 44(11): 2146-2155.
[4]	Li MEI, Lu ZHANG, Di WU, Huanzhang DING, Xinru WANG, Xian ZHANG, Yuhang WEI, Zegeng LI, Jiabing TONG. Liuwei Buqi Formula delays progression of chronic obstructive pulmonary disease in rats by regulating the NLRP3/caspase-1/GSDMD pyroptosis pathway [J]. Journal of Southern Medical University, 2024, 44(11): 2156-2162.
[5]	Qinjun YANG, Hui WANG, Shuyu XU, Cheng YANG, Huanzhang DING, Di WU, Jie ZHU, Jiabing TONG, Zegeng LI. Shenqi Tiaoshen Formula alleviates airway inflammation in rats with chronic obstructive pulmonary disease and kidney qi deficiency syndrome by inhibiting ferroptosis via regulating the Nrf2/SLC7A11/GPX4 signaling pathway [J]. Journal of Southern Medical University, 2024, 44(10): 1937-1946.
[6]	Mengmeng CHENG, Xinguang LIU, Yanxin WEI, Xiaoxiang XING, Lan LIU, Nan XIN, Peng ZHAO. Tongsai Granules inhibit autophagy and macrophage-mediated inflammatory response to improve acute exacerbations of chronic obstructive pulmonary disease in rats [J]. Journal of Southern Medical University, 2024, 44(10): 1995-2003.
[7]	XU Guiling, GONG Zhaoqian, WANG Junrao, MA Yanyan, XU Maosheng, CHEN Meijia, HU Dapeng, LIANG Jianpeng, ZHAO Wengqu, ZHAO Haijin. Effects of type 2 inflammation on bronchodilator responsiveness of large and small airways in chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2024, 44(1): 93-99.
[8]	LIU Ze, HE Wenxia, FANG Ruizhe, XIAO Gang, YAN Fang, QIU Qiguang, FANG Huilong, WANG Junjie. Lifetide biofeedback intervention in type 2 diabetic patients: a pilot observation [J]. Journal of Southern Medical University, 2023, 43(9): 1622-1628.
[9]	WU Di, WANG Xiaole, GAO Yating, TONG Jiabing, YANG Qinjun, DING Huanzhang, ZHANG Lu, LI Zegeng. Shenqi Wenfei Formula alleviates chronic obstructive pulmonary disease in rats with pulmonary qi deficiency syndrome by regulating NLRP3/GSDMD pyroptosis pathway [J]. Journal of Southern Medical University, 2023, 43(9): 1500-1508.
[10]	WEI Ke, SHI Jiwen, XIAO Yuhan, WANG Wenrui, YANG Qingling, CHEN Changjie. MiR-30e-5p overexpression promotes proliferation and migration of colorectal cancer cells by activating the CXCL12 axis via downregulating PTEN [J]. Journal of Southern Medical University, 2023, 43(7): 1081-1092.
[11]	WANG Min, ZHANG Qian, XU Guiling, HUANG Shuyu, ZHAO Wenqu, LIANG Jianpeng, HUANG Junwen, CAI Shaoxi, ZHAO Haijin. Association between vitamin D level and blood eosinophil count in healthy population and patients with chronic obstructive pulmonary disease [J]. Journal of Southern Medical University, 2023, 43(5): 727-732.
[12]	XU Chen, LI Chunying, WANG Sheng. Yifei Jianpi recipe improves cigarette smoke-induced inflammatory injury and mucus hypersecretion in human bronchial epithelial cells by inhibiting the TLR4/NF-κB signaling pathway [J]. Journal of Southern Medical University, 2023, 43(4): 507-515.
[13]	ZHOU Bei, LI Jing, FANG Chenyuan, HUANG Yanan, SANG Guirui, TAO Shaoping, HE Chunling. Comparison of therapeutic effect of metformin hydrochloride/vildagliptin and liraglutide on type 2 diabetes mellitus in obese patients [J]. Journal of Southern Medical University, 2023, 43(3): 436-442.
[14]	LIU Zhiyu, FANG Fengzhu, LI Jing, ZHAO Guangyue, ZANG Quanjin, ZHANG Feng, DIE Jun. RHPN2 is highly expressed in osteosarcoma cells to promote cell proliferation and migration and inhibit apoptosis [J]. Journal of Southern Medical University, 2022, 42(9): 1367-1373.
[15]	SHI Xiuru, WEI Ke, WU Yulun, WANG Wenrui, YANG Qingling, CHEN Changjie. MiR-372-5p regulates PI3K/AKT/CXCL12 signaling pathway by targeting PTEN to promote colorectal cancer cell metastasis [J]. Journal of Southern Medical University, 2022, 42(8): 1191-1197.