High Expression of DLGAP5 Indicates Poor Prognosis and Immunotherapy in Lung Adenocarcinoma and Promotes Proliferation through Regulation of the Cell Cycle

Abstract

Background. Lung adenocarcinoma (LUAD) is one of the most common types of cancer in the respiratory system, with a high mortality and recurrence rate. The role of disc large-associated protein 5 (DLGAP5) in LUAD progression and tumor microenvironment (TME) remains unclear. This study is aimed at revealing the functional role of DLGAP5 in LUAD based on bioinformatics analysis and experimental validation. Methods. Differential expression analysis, protein-protein interaction (PPI) network, and Cox regression analysis were applied to screen potential prognostic biomarkers. The mRNA and protein levels of DLGAP5 were analyzed using The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. The CCK-8 and colony formation assays were performed to assess the effect of DLGAP5 on cell proliferation. RNA sequencing (RNA-seq) and enrichment analyses were utilized to explore the biological functions of DLGAP5. Furthermore, flow cytometry was used to explore the role of DLGAP5 on the cell cycle. The ssGSEA algorithm in the R package “GSVA” was applied to quantify immune infiltrating cells, and the tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict the efficacy of immunotherapy. Moreover, analyses using the cBioPortal and MethSurv databases were performed to evaluate the mutation and methylation of DLGAP5, respectively. Finally, the prognostic value of DLGAP5 was estimated using the TCGA and the Gene Expression Omnibus (GEO) databases. The nomogram model was constructed using the TCGA-LUAD cohort and evaluated by adopting calibration curves, time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results. DLGAP5 mRNA and protein abundance were significantly elevated in LUAD, and knockdown of DLGAP5 remarkably suppressed lung cancer cell proliferation through induction of cell cycle G1 arrest. In addition, DLGAP5 expression was positively correlated with Th2 cells and negatively correlated with B cells, T follicular helper cells, and mast cells. LUAD patients with high DLGAP5 expression may be resistant to immunotherapy. Hypermethylation levels of the cg23678254 site of DLGAP5 or its enhanced expression were unfavorable for the survival of LUAD patients. Meanwhile, DLGAP5 expression was associated with TNM stages, tumor status, and therapy outcome. Notably, the prognostic model constructed based on DLGAP5 expression exhibited great predictive capability, which was promising for clinical applications. Conclusion. DLGAP5 promotes lung cancer cell proliferation through regulation of the cell cycle and is associated with multiple immune infiltrating cells. Furthermore, DLGAP5 predicts poor prognosis and response to immunotherapy in lung adenocarcinoma.

DLGAP5 promotes lung adenocarcinoma growth via upregulating PLK1 and serves as a therapeutic target

“…In vitro, we also exhibited that DLGAP5 overexpression promoted cell proliferation of LUAD, while DLGAP5 knockdown showed the opposite effect. These findings were similar with previous reports [ 11 , 38 ], jointly supporting that DLGAP5 may promote LUAD development and be a promising prognostic biomarker for LUAD.…”

“…There is evidence that DLGAP5 contributes to tumorigenesis and progression of numerous cancer types, for example, bladder cancer [ 34 ], endometrial cancer [ 35 ], ovarian cancer [ 36 ] and lung cancer [ 37 , 38 ]. In our current study, we conducted bioinformatics, network pharmacology analysis and experimental study to gain a more comprehensive understanding of the potential functions and regulatory mechanisms of DLGAP5 in LUAD.…”

Machine learning-based integrated identification of predictive combined diagnostic biomarkers for endometriosis

“…DLGAP5 is considered an adverse prognostic biomarker in certain diseases, particularly cancer. Its aberrant expression may lead to abnormal cell division, promoting tumour growth and metastasis ( Shen et al, 2023 ; Tang et al, 2023 ). In the context of endometriosis research, DLGAP5 may be involved in cellular proliferation and differentiation processes, further influencing the development and progression of the disease.…”

DLGAP5 Regulates the Proliferation, Migration, Invasion, and Cell Cycle of Breast Cancer Cells via the JAK2/STAT3 Signaling Axis

“…It not only supports microtubule growth and stability in the spindle [11] but also acts as an oncogenic cell cycle regulator, playing a crucial role in tumor development and metastasis [12][13][14]. DLGAP5 has been reported as an underlying prognostic factor in lung cancer, BC, clear cell renal cell carcinoma, and colorectal cancer and the overexpression of DLGAP5 has been proved to be linked to poor prognosis in these cancers [15][16][17][18][19][20][21]. Tang et al [22] have reached a similar conclusion by pan-cancer analysis.…”