Serum-derived extracellular vesicles promote the growth and metastasis of non-small cell lung cancer by delivering the m6A methylation regulator HNRNPC through the regulation of DLGAP5

Shi, Shanshan; Wu, Tong; Ma, Zechen; Zhang, Xiudi; Xu, Ke; Tian, Qi; Gao, Lian; Yin, Xi‐Jun; Xu, Shufeng; Yang, Shengbo

doi:10.1007/s00432-022-04375-6

Cited by 8 publications

(5 citation statements)

References 40 publications

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“…This suggested that the mechanism of m6A methylation may be crucial in regulating DLGAP5 expression in LUAD. Another study reported that the m6A methylation regulator heterogeneous nuclear ribonucleoprotein C (HNRNPC) promotes the growth and metastasis of non-small cell lung cancer through its regulation of DLGAP5 (Shi et al, 2022), which supports our findings. There may be additional mechanisms, such as chromosomal histone modification or RNA m1A/m5C modification, that contribute to the upregulation of DLGAP5 in LUAD.…”

Section: Discussionsupporting

confidence: 90%

Analysis of functional hub genes indicates DLGAP5 is linked to lung adenocarcinoma prognosis

ZHENG,

LIN,

CAI

et al. 2023

BIOCELL

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Introduction:The difficulty in treating lung adenocarcinoma (LUAD) is caused by a shortage of knowledge about the biological mechanisms and a lack of treatment choices. Objectives: The aim of this study was to identify a valuable molecular target for the treatment of LUAD. Methods: Using multiple databases, we screened for hub genes in LUAD using Cytoscape and explored the expression and prognosis of DLG associated protein 5 (DLGAP5) in LUAD. We investigated the genetic variation, functional enrichment, and epigenetic activity of DLGAP5. Furthermore, we evaluated the relationship between the tumor microenvironment (TME) and DLGAP5. Results: Our study identified 10 hub genes in LUAD: CDC45, KIAA0101, DLGAP5, CDT1, NCAPG, CCNB1, CDCA5, CDC20, KIF11, and AURKA. We discovered that DLGAP5 was overexpressed and associated with poor prognosis in LUAD.DLGAP5 exhibited an overall genetic variation frequency of 2%, and its DNA promoter was hypomethylated in LUAD (p < 0.05). The expression of DLGAP5 in LUAD showed a positive correlation with the majority of N6methyladenosine (m6A)-methylation genes. Additionally, DLGAP5 was primarily associated with the cell cycle in LUAD. Notably, there was a significant favorable association between DLGAP5 and CD274, CTLA4, HAVCR2, and LAG3 in LUAD. Conclusion: DLGAP5 may be a therapeutic target for LUAD, as it affects cancer cells proliferation and development through the regulation of cell-cycle checkpoints and modulation of immune cell infiltration and immune checkpoints in the TME.

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Section: Discussionsupporting

confidence: 90%

Analysis of functional hub genes indicates DLGAP5 is linked to lung adenocarcinoma prognosis

ZHENG,

LIN,

CAI

et al. 2023

BIOCELL

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Chen,

Zhang,

Wang

et al. 2024

J Transl Med

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Background Human discs large-associated protein 5 (DLGAP5) is reported to play a pivotal role in regulating the cell cycle and implicate in tumorigenesis and progression of various cancers. Our current research endeavored to explore the prognostic value, immune implication, biological function and targeting strategy of DLGAP5 in LUAD through approaches including bioinformatics, network pharmacology analysis and experimental study. Methods Multiple databases, including TCGA, GEO, CPTAC and Human Protein Atlas, were utilized to explore the expression and clinical significance of DLGAP5 in LUAD. The genetic alterations of DLGAP5 were assessed through cBioPortal and COSMIC databases. The relationship between DLGAP5 expression and genetic abnormalities of driver genes in LUAD was analyzed through TIMER2.0 database. CancerSEA database was utilized to explore the function of DLGAP5 in 14 different states in LUAD at single-cell resolution. GDSC database was utilized to analyze the impact of DLGAP5 on IC50 of frequently-used anti-LUAD drugs. CIBERSORT method and TIMER2.0 database was utilized to explore the relationship between DLGAP5 and tumor immune infiltration. Network pharmacology was applied to screen potential DLGAP5 inhibitor. In vitro and in vivo experiments were utilized to evaluate biological function and downstream targets of DLGAP5, and the effect of screened DLGAP5 inhibitor on LUAD growth. Results High DLGAP5 expression was commonly observed in LUAD and associated with mutation of major driver genes, poor prognosis, high IC50 values of frequently-used anti-LUAD drugs, increasing immune infiltration and elevated immune checkpoint blockade-related genes in LUAD. PLK1 was revealed as a potential DLGAP5 downstream target in LUAD. DLGAP5 overexpression or knockdown significantly promoted or inhibited LUAD cell proliferation and PLK1 expression. PLK1 overexpression well rescued DLGAP5 knockdown-induced cell proliferation inhibition, or vice versa. Furthermore, by virtual screening of an investigational drug library from the DrugBank database, AT9283 was screened and identified as a novel DLGAP5 inhibitor. AT9283 effectively suppressed growth of LUAD cells both in vitro and in vivo. DLGAP5 overexpression significantly reversed AT9283-induced proliferation inhibition. Moreover, AT9283 significantly suppressed DLGAP5 and PLK1 expression, while DLGAP5 overexpression significantly reversed AT9283-induced PLK1 suppression. Conclusion Our research has demonstrated that DLGAP5 is upregulated in LUAD and exhibits a strong correlation with unfavorable prognosis. Furthermore, DLGAP5 assumes a significant function in the regulation of tumor immunity and treatment outcome of immune checkpoint inhibitors. Of note, we found that DLGAP5 promotes cell proliferation of LUAD via upregulating PLK1. Targeting DLGAP5 by AT9283, our newly identified DLGAP5 inhibitor, suppresses LUAD growth. DLGAP5 may become a promising prognostic biomarker and therapeutic target for patients with LUAD.

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“…Subsequent survival analyses suggested that high expression of both METTL3 and YTHDF1 suggested a poor prognosis and lung cancer patients with high expression of both METTL3 and YTHDF1 had the worst clinical prognosis. Further gene set enrichment analyses showed that both may regulate lung cancer value-added through pathways such as RNA metabolic processes, DNA replication and cell cycle [18].…”

Section: Discussionmentioning

confidence: 99%

Expression patterns and prognostic role of m6A RNA methylation regulators in Non-small Cell Lung Cancer

Ming Zhang,

Congbo Yang,

Wen Dong

et al. 2024

Cell Mol Biol (Noisy-le-grand)

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The purpose of this study was to investigate the expression pattern and prognostic role of m6A RNA methylation regulators in non-small cell lung cancer (NSCLC), we downloaded data from 422 patients from The Cancer Genome Atlas (TCGA) database. The relationship between the expression levels of m6A RNA methylation regulators and clinicopathological variables of NSCLC was analysed using R language. By analysing glioma data in TCGA, we found that a prognostic risk score model could be constructed based on 18 genes with m6A methylation modification. m6A gene alterations were significantly associated with tumour grade and tumour stage. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression models were used to identify 2 m6A RNA methylation modifiers: IFG2BP2, and METTL14 to construct risk profiles. Based on the risk profile, patients were divided into high-risk and low-risk groups. The overall survival rate of the low-risk group was significantly higher than that of the high-risk group. The results suggest that the prognostic risk score model constructed by m6A methylation regulators can predict the prognosis of glioma patients. IFG2BP2 and METTL14 may be the key m6A methylation regulators involved in the development of NSCLC and can be used as the molecular markers for the prognosis of NSCLC.

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Serum-derived extracellular vesicles promote the growth and metastasis of non-small cell lung cancer by delivering the m6A methylation regulator HNRNPC through the regulation of DLGAP5

Cited by 8 publications

References 40 publications

Analysis of functional hub genes indicates DLGAP5 is linked to lung adenocarcinoma prognosis

Analysis of functional hub genes indicates DLGAP5 is linked to lung adenocarcinoma prognosis

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

Expression patterns and prognostic role of m6A RNA methylation regulators in Non-small Cell Lung Cancer

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