Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer

Dong, Zhexu; Dai, Lei; Zhang, Yong; Fang, Chao; Shi, Gang; Chen, Ye; Li, Junshu; Wang, Qin; Fu, Jiayi; Yu, Yan; Wang, Wenshuang; Cheng, Lin; Liu, Yi; Lin, Yi; Wang, Yuan; Wang, Qingnan; Wang, Huiling; Zhang, Hantao; Zhang, Yujing; Su, Xiaolan; Zhang, Shuang; Wang, Feng; Meng, Qingcai; Zhou, Zong‐Guang; Deng, Hongxin

doi:10.1371/journal.pgen.1009159

Cited by 10 publications

(5 citation statements)

References 56 publications

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“…The development of immunotherapy has triggered an increasing number of investigations into the clinical efficacy of targeting immune checkpoints, including early diagnosis, combination therapy, and treatment prediction in patients with various types of tumors. Individual neurotrophic factor family members are now considered to be biomarkers for predicting cancer development and prognosis ( 57 ). Overactivation of the immune system concurrently can induce or stimulate the onset of neurodegeneration and cancer, as well as local or systemic inflammatory reactions ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

et al. 2023

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BackgroundGlioblastoma multiforme (GBM) is the most common cancer of the central nervous system, while Parkinson’s disease (PD) is a degenerative neurological condition frequently affecting the elderly. Neurotrophic factors are key factors associated with the progression of degenerative neuropathies and gliomas.MethodsThe 2601 neurotrophic factor-related genes (NFRGs) available in the Genecards portal were analyzed and 12 NFRGs with potential roles in the pathogenesis of Parkinson’s disease and the prognosis of GBM were identified. LASSO regression and random forest algorithms were then used to screen the key NFRGs. The correlation of the key NFRGs with immune pathways was verified using GSEA (Gene Set Enrichment Analysis). A prognostic risk scoring system was constructed using LASSO (Least absolute shrinkage and selection operator) and multivariate Cox risk regression based on the expression of the 12 NFRGs in the GBM cohort from The Cancer Genome Atlas (TCGA) database. We also investigated differences in clinical characteristics, mutational landscape, immune cell infiltration, and predicted efficacy of immunotherapy between risk groups. Finally, the accuracy of the model genes was validated using multi-omics mutation analysis, single-cell sequencing, QT-PCR, and HPA.ResultsWe found that 4 NFRGs were more reliable for the diagnosis of Parkinson’s disease through the use of machine learning techniques. These results were validated using two external cohorts. We also identified 7 NFRGs that were highly associated with the prognosis and diagnosis of GBM. Patients in the low-risk group had a greater overall survival (OS) than those in the high-risk group. The nomogram generated based on clinical characteristics and risk scores showed strong prognostic prediction ability. The NFRG signature was an independent prognostic predictor for GBM. The low-risk group was more likely to benefit from immunotherapy based on the degree of immune cell infiltration, expression of immune checkpoints (ICs), and predicted response to immunotherapy. In the end, 2 NFRGs (EN1 and LOXL1) were identified as crucial for the development of Parkinson’s disease and the outcome of GBM.ConclusionsOur study revealed that 4 NFRGs are involved in the progression of PD. The 7-NFRGs risk score model can predict the prognosis of GBM patients and help clinicians to classify the GBM patients into high and low risk groups. EN1, and LOXL1 can be used as therapeutic targets for personalized immunotherapy for patients with PD and GBM.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

et al. 2023

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“…Interestingly, the downregulation of NDRG2 could be modulating the activation of PI3K/Akt signaling in oral carcinogenesis (Furuta et al, 2010). The GFRA1 gene displays an important role in tumor progression and metastasis (Cavel et al, 2012; Dong et al, 2020; Esseghir et al, 2007), and its methylation has been described in rectal (Wei et al, 2016), lung (Sato et al, 2013), and gastric (Liu et al, 2014) cancer. Also, aberrant methylation of GABRB3 and ACSS3 genes has been previously reported in head and neck (Guerrero‐Preston et al, 2014) and prostate (Zhou, Song, et al, 2021) cancer.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide DNA methylation profiling in tongue squamous cell carcinoma

et al. 2022

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ObjectivesTo provide a comprehensive characterization of DNA methylome of oral tongue squamous cell carcinoma (OTSCC) and identify novel tumor‐specific DNA methylation markers for early detection using saliva.Material and MethodsGenome‐wide DNA methylation analysis including six OTSCC matched adjacent non‐tumoral tissue and saliva was performed using Infinium MethylationEPIC array. Differentially methylated levels of selected genes in our OTSCC cohort were further validated using OTSCC methylation data from The Cancer Genome Atlas database (TCGA). The methylation levels of a set of tumor‐specific hypermethylated genes associated with a downregulated expression were evaluated in saliva. Receiver operating characteristic (ROC) curves were performed to assess the diagnostic value of DNA methylation markers.ResultsA total of 25,890 CpGs (20,505 hypomethylated and 5385 hypermethylated) were differentially methylated (DMCpGs) between OTSCC and adjacent non‐tumoral tissue. Hypermethylation of 11 tumor‐specific genes was validated in OTSCC TCGA cohort. Of these 11 genes, A2BP1, ANK1, ALDH1A2, GFRA1, TTYH1, and PDE4B were also hypermethylated in saliva. These six salivary methylated genes showed high diagnostic accuracy (≥0.800) for discriminating patients from controls.ConclusionsThis is the first largest genome‐wide DNA methylation study on OTSCC that identifies a group of novel tumor‐specific DNA methylation markers with diagnostic potential in saliva.

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“…In tumor cells, oncogenes are in a state of hypomethylation, and so they are activated. Abnormal hypomethylation of some genes, such as mothers against decapentaplegic homolog 3 (SMAD3), long interspersed nucleotide element-1 (LINE-1) and GDNF family receptor alpha 1 (GFRA1) genes, have been shown to be associated with the poor prognosis of CRC [31][32][33].…”

Section: Epigenetics In Crcmentioning

confidence: 99%

Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer

2021

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Cellular metabolism alterations have been recognized as one of the most predominant hallmarks of colorectal cancers (CRCs). It is precisely regulated by many oncogenic signaling pathways in all kinds of regulatory levels, including transcriptional, post-transcriptional, translational and post-translational levels. Among these regulatory factors, epigenetics play an essential role in the modulation of cellular metabolism. On the one hand, epigenetics can regulate cellular metabolism via directly controlling the transcription of genes encoding metabolic enzymes of transporters. On the other hand, epigenetics can regulate major transcriptional factors and signaling pathways that control the transcription of genes encoding metabolic enzymes or transporters, or affecting the translation, activation, stabilization, or translocation of metabolic enzymes or transporters. Interestingly, epigenetics can also be controlled by cellular metabolism. Metabolites not only directly influence epigenetic processes, but also affect the activity of epigenetic enzymes. Actually, both cellular metabolism pathways and epigenetic processes are controlled by enzymes. They are highly intertwined and are essential for oncogenesis and tumor development of CRCs. Therefore, they are potential therapeutic targets for the treatment of CRCs. In recent years, both epigenetic and metabolism inhibitors are studied for clinical use to treat CRCs. In this review, we depict the interplay between epigenetics and cellular metabolism in CRCs and summarize the underlying molecular mechanisms and their potential applications for clinical therapy.

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Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer

Cited by 10 publications

References 56 publications

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

Genome‐wide DNA methylation profiling in tongue squamous cell carcinoma

Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer

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