A network-based approach to identify DNA methylation and its involved molecular pathways in testicular germ cell tumors

Bo, Hao; Cao, Ke; Tang, Ruiling; Zhang, Han; Gong, Zhaojian; Liu, Zhizhong; Liu, Jianye; Li, Jingjing; Fan, Liqing

doi:10.7150/jca.27491

Cited by 14 publications

(13 citation statements)

References 68 publications

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“…Furthermore, locus specific promoter methylation occurs in nonseminoma that is distinct for each histological type, again with a general pattern of increased methylation with increased differentiation status [ 25 , 101 , 102 ]. This includes evidence that methylation of such genes as CRIPTO , HOXA9 MGMT , RASSFIA , SCGB3A1 , CALCA , MMP9 , CSFR1 , and PTPRC is associated with distinct TGCT subtypes or poor prognosis [ 101 , 114 , 115 , 116 , 118 ].…”

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Singh

Fazal

Freemantle

et al. 2021

Cancers

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Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. Decades of focus on genomic alterations in TGCTs including awareness of a near universal increase in copies of chromosome 12p have failed to uncover exceptional driver genes, especially in genes that can be targeted therapeutically. Thus far, TGCT patients have missed out on the benefits of targeted therapies available to treat most other malignancies. In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. While genetics undoubtedly plays a role in TGCT biology, this mini-review will focus on the epigenetic “states” or features of testicular cancer, with an emphasis on DNA methylation, histone modifications, and miRNAs associated with TGCT susceptibility, initiation, progression, and response to chemotherapy. In addition, we comment on the current status of epigenetic-based therapy and epigenetic biomarker development for TGCTs. Finally, we suggest a unifying “rock and a hard place” or “differentiate or die” model where the tumorigenicity and curability of TGCTs are both dependent on common but still ill-defined epigenetic states.

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Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Singh

Fazal

Freemantle

et al. 2021

Cancers

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“…At present, few bioinformatics analyses have been conducted to investigate DEGs and DEMs in seminoma. Of the DEGs screened in this study, only TOP2A and PTPRC have been reported in seminoma (59,60), to the best of our knowledge. Additionally, we screened the differential expression of genes from array data and predicted target genes of DEMs which were proposed to act together on the PI3K/AKT and Wnt/β-catenin signalling pathways with a strong correlation (29,39).…”

Section: Discussionmentioning

confidence: 89%

Identification of potential core genes and miRNAs in testicular seminoma via bioinformatics analysis

et al. 2019

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Testicular seminoma is one of the most common tumours in the field of urology, and its aetiology is still unclear. The aim of the present study was to identify the factors responsible for the development of testicular cancer and to investigate whether mutations in these genes were primarily congenital or acquired. To identify the key genes and miRNAs linked to testicular seminoma, as well as their potential molecular mechanisms, the GSE15220, GSE1818 and GSE59520 microarray datasets were analysed. A total of 5,195 and 1,163 differentially expressed genes (DEGs) were identified after analysing the GSE15220 and GSE1818 datasets, respectively. Among them, 287 genes were common between the two datasets. Of these, 110 were upregulated and 177 were downregulated. Five differentially expressed microRNAs (miRs; DEMs) that were downregulated in seminoma were identified after analysing the GSE59520 dataset. Following protein-protein interaction network and Gene Ontology analysis, the five nodes with the highest degrees were screened as hub genes. Among them, the high expression of hub genes, such as protein tyrosine phosphatase receptor type C (PTPRC), was associated with worse overall survival. We also predicted the potential target genes of the DEMs. DNA topoisomerase II α (TOP2A), marker of proliferation Ki-67 (MKI67), PTPRC and ubiquitin conjugating enzyme E2 C were associated with the PI3K/AKT and Wnt/β-catenin signalling pathways. In addition, hsa-miR-650 and hsa-miR-665 were associated with the PI3K/AKT and Wnt/β-catenin signalling pathways. Additionally, TOP2A and MKI67 were strongly associated with the target genes hsa-miR-650 and hsa-miR-665, respectively. We proposed that the hub genes reported in the present study may have a certain impact on cellular proliferation and migration in testicular seminoma. The roles of these hub genes in seminoma may provide novel insight to improve the diagnosis and treatment of patients with seminoma.

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“…TGCT occurs in young men, posing a huge threat to the life and reproductive health of young male patients, but the pathogenesis has not been fully elucidated. Many studies have shown that genetic factors and epigenetic factors are closely related to the occurrence and development of TGCT 25 – 27 . METTL3 is an important molecule that regulates m6A modification in epigenetics and can initiate meiosis by promoting the differentiation process of spermatogenesis 28 .…”

Section: Discussionmentioning

confidence: 99%

METTL3 May Regulate Testicular Germ Cell Tumors Through EMT and Immune Pathways

Luo

Sun

et al. 2020

Cell Transplant

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Testicular germ cell tumors (TGCTs) are highly prevalent in young men aged 20–40 years and are one of the most common lethal solid tumors in men of this age. Due to the current unclear mechanism of tumor development, there is a lack of effective treatment, and therefore in-depth research of the molecular mechanism of the occurrence and development of TGCT and the search for suitable and effective therapeutic targets and molecular markers are of great significance for achieving effective treatment. METTL3 is a very important methylase, which has been implicated in the progression of many cancers, but the role of METTL3 in TGCT has not been fully elucidated. In this article, we found that METTL3 expression was significantly downregulated in TGCT tissues, and patients with low expression levels had lower overall survival and relapse-free survival rates. After overexpressing METTL3, cell proliferation, invasion, and migration ability significantly increased, while influencing the expression of epithelial–mesenchymal transition (EMT)-related proteins. In addition, we observed that the expression level of METTL3 positively correlated with molecular markers and infiltration level of CD8+ and CD4+ T cells and natural killer cells. In sum, our findings identified that METTL3 can be used as an independent prognostic marker in patients with TGCT. METTL3 participates in the proliferation, migration, and invasion of TGCT cells by regulating the expression of EMT-related genes and may also play a role in activating the tumor immune response in TGCT.

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A network-based approach to identify DNA methylation and its involved molecular pathways in testicular germ cell tumors

Cited by 14 publications

References 68 publications

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Identification of potential core genes and miRNAs in testicular seminoma via bioinformatics analysis

METTL3 May Regulate Testicular Germ Cell Tumors Through EMT and Immune Pathways

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