Epigenetic Regulation of CD133 in Gastrointestinal Stromal Tumors

Geddert, Helene; Braun, Alexander; Kayser, Claudia; Dimmler, Arno; Faller, Gerhard; Agaimy, Abbas; Haller, Florian; Moskalev, Evgeny A.

doi:10.1093/ajcp/aqx028

Cited by 13 publications

(14 citation statements)

References 35 publications

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“…DNA methylation also limits the accessibility of Sp1 and Myc to the CD133 promoter and subsequently regulate CD133 expression (Gopisetty, Xu, Sampath, Colman, & Puduvalli, 2013). Also, CD133 hypomethylation is a prognostically adverse finding in gastrointestinal stromal tumors (Geddert et al, 2017). In another study, Yi et al combined DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) and radiation for the treatment of pancreatic cancer.…”

Section: Regulation Of Cd133 Expressionmentioning

confidence: 99%

New emerging roles of CD133 in cancer stem cell: Signaling pathway and miRNA regulation

Aghajani

Mansoori

Mohammadi

et al. 2019

Journal Cellular Physiology

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Cancer stem cells (CSC) are rare immortal cells within a tumor that are able to initiate tumor progression, development, and resistance. Advances studies show that, like normal stem cells, CSCs can be both self-renewed and given rise to many cell types, therefore form tumors. A number of cell surface markers, such as CD44, CD24, and CD133 are frequently used to identify CSCs. CD133, a transmembrane glycoprotein, either alone or in collaboration with other markers, has been mainly considered to identify CSCs from different solid tumors. However, the exactness of CD133 as a cancer stem cell biomarker has not been approved yet. The clinical importance of CD133 is as a CSC marker in many cancers. Also, it contributes to shorter survival, tumor progression, and tumor recurrence. The expression of CD133 is controlled by many extracellular or intracellular factors, such as tumor microenvironment, epigenetic factors, signaling pathways, and miRNAs. In this study, it was attempted to determine: 1) CD133 function; 2) the role of CD133 in cancer; 3) CD133 regulation; 4) the therapeutic role of CD133 in cancers.

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Section: Regulation Of Cd133 Expressionmentioning

confidence: 99%

New emerging roles of CD133 in cancer stem cell: Signaling pathway and miRNA regulation

Aghajani

Mansoori

Mohammadi

et al. 2019

Journal Cellular Physiology

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“…Recently, numerous studies have implied that epigenetic alterations play critical roles in a wide range of tumours [ 9 , 10 ]. Previous studies have also demonstrated that epigenetic alterations are responsible for GIST development [ 11 ]. Both DNA hypomethylation and DNA hypermethylation are reported to be closely related to GIST progression.…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling

Liu

et al. 2018

Mol Cancer

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BackgroundGastrointestinal stromal tumour (GIST) is the most common soft tissue sarcoma. The identification of the molecular mechanisms regulating GIST progression is vital for its treatment and prevention. Increasing reports have demonstrated that epigenetic alterations play critical roles in GIST development. However, the role of the histone demethylase KDM4D in GIST progression is poorly understood.MethodsIn clinically matched GIST tissues, KDM4D protein levels were measured by Western blot and immunohistochemical (IHC) staining. KDM4D mRNA levels were examined by quantitative real-time PCR (qRT-PCR). Bioinformatics analysis was used to examine KDM4D expression. The biological effects of KDM4D were investigated in vitro using CCK-8, BrdU/PI, wound healing, colony formation, tube formation and Transwell assays and in vivo using a xenograft mice model. Luciferase assays were used to assess regulation of HIF1β gene promoter activity by KDM4D. ChIP assays were performed to assess KDM4D, H3K36me3 and H3K9me3 occupancy on the HIF1β gene promoter.ResultsWe observed a significant upregulation of KDM4D in GIST tissue compared with matched normal tissue and further explored the oncogenic function of KDM4D both in vitro and in vivo. Furthermore, we demonstrated that KDM4D directly interacted with the HIF1β gene promoter and regulated its activity, promoting tumour angiogenesis and GIST progression both in vitro and in vivo. Finally, we demonstrated that KDM4D transcriptionally activates HIF1β expression via H3K9me3 and H3K36me3 demethylation at the promoter region.ConclusionsOur findings reveal the important roles of the KDM4D/HIF1β/VEGFA signalling pathway in GIST progression, and this pathway may act as a potential therapeutic target for GIST patients.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0861-6) contains supplementary material, which is available to authorized users.

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“…Multiple transcript variants of PROM1 encoding different isoforms have been described [71]. Immunostaining in consecutive tissues using different PROM1 antibodies showed different protein expressions and characteristics [72]. GBM tumors, initiated directly from biopsies and engrafted intracerebrally into nude rats, expressed little or no PROM1 [73].…”

Section: Discussionmentioning

confidence: 99%

Array expression meta-analysis of cancer stem cell genes identifies upregulation of PODXL especially in DCC low expression meningiomas

Schulten

Hussein

2019

PLoS ONE

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Background Meningiomas are the most common intracranial tumors, with a subset of cases bearing a progressive phenotype. The DCC netrin 1 receptor ( DCC ) is a candidate gene for early meningioma progression. Cancer stem cell (CSC) genes are emerging as cancer therapeutic targets, as their expression is frequently associated with aggressive tumor phenotypes. The main objective of the study was to identify deregulated CSC genes in meningiomas. Materials and methods Interrogating two expression data repositories, significantly differentially expressed genes (DEGs) were determined using DCC low vs . DCC high expression groups and WHO grade I (GI) vs . grade II + grade III (GII + GIII) comparison groups. Human stem cell (SC) genes were compiled from two published data sets and were extracted from the DEG lists. Biofunctional analysis was performed to assess associations between genes or molecules. Results In the DCC low vs . DCC high expression groups, we assessed seven studies representing each between seven and 58 samples. The type I transmembrane protein podocalyxin like ( PODXL ) was markedly upregulated in DCC low expression meningiomas in six studies. Other CSC genes repeatedly deregulated included, e . g ., BMP/retinoic acid inducible neural specific 1 ( BRINP1 ), prominin 1 ( PROM1 ), solute carrier family 24 member 3 ( SLC24A3 ), rRho GTPase activating protein 28 ( ARHGAP28 ), Kruppel like factor 5 ( KLF5 ), and leucine rich repeat containing G protein-coupled receptor 4 ( LGR4 ). In the GI vs . GII + GIII comparison groups, we assessed six studies representing each between nine and 68 samples. DNA topoisomerase 2-alpha ( TOP2A ) was markedly upregulated in GII + GIII meningiomas in four studies. Other CSC genes repeatedly deregulated included, e . g ., ARHGAP28 and PODXL . Network analysis revealed associations of molecules with, e . g ., cellular development and movement; nervous system development and function; and cancer. Conclusions This meta-analysis on meningiomas identified a comprehensive list of deregulated CSC genes across different array expression studies. Especially, PODXL is of interest for functional assessment in progressive meningiomas.

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Epigenetic Regulation of CD133 in Gastrointestinal Stromal Tumors

Abstract: Our results strongly suggest epigenetic regulation of CD133 expression by promoter methylation in GISTs. Pending further validation studies, high abundance of the protein can serve as a marker for malignant GISTs.

Cited by 13 publications

References 35 publications

New emerging roles of CD133 in cancer stem cell: Signaling pathway and miRNA regulation

New emerging roles of CD133 in cancer stem cell: Signaling pathway and miRNA regulation

Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling

Array expression meta-analysis of cancer stem cell genes identifies upregulation of PODXL especially in DCC low expression meningiomas

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