RUNX3 is inactivated by promoter hypermethylation in malignant transformation of ovarian endometriosis

Guo, Cuishan; Ren, Fang; Wang, Danbo; Li, Yan; Liu, Kuiran; Liu, Shuang; Chen, Peng

doi:10.3892/or.2014.3524

Cited by 21 publications

(13 citation statements)

References 34 publications

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“…Interestingly, methylation levels of these two sites were correlated with each other (r=0.822, p<0.001) However, only the degree of methylation at the transcription start had a direct correlation with lower RUNX3 expression (r=−0.429, p=0.029) (see online supplementary table S2). We did not observe a difference in methylation patterns between men and women (data not shown); this is noteworthy since oestrogen has been suggested to be able to regulate RUNX3 methylation patterns 23. Next, we isolated pDCs from patients with SSc and cultured them in the presence of demethylating agent 5-Aza-CdR (figure 2C).…”

Section: Resultsmentioning

confidence: 75%

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

Affandi¹,

Carvalheiro²,

Ottria³

et al. 2019

Ann Rheum Dis

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ObjectivesSystemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology.MethodsIn total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre:Runx3f/f mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model.ResultsHere, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis.ConclusionsWe show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease.

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Section: Resultsmentioning

confidence: 75%

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

Affandi¹,

Carvalheiro²,

Ottria³

et al. 2019

Ann Rheum Dis

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“…Paralleling RUNX1, RUNX2 is hypomethylated in post-CT samples from HGSOC patients [75] and a correlation between RUNX2 overexpression, tumour progression and poor disease diagnosis in ovarian cancer has been described [135]. Contradictory evidence of both a tumour suppressor and a tumour promoter has been reported for RUNX3, which is hypermethylated [136,137], as well as overexpressed [138] in ovarian cancer. In terms of the uterus, Runx3, like Runx1, may have a role in the normal physiology of the organ [134], but unlike the pro-oncogenic properties of RUNX1 (see above), it seems that inactivation of RUNX3 is linked to endometrial carcinoma [139].…”

Section: The Runx1 'Siblings' In Female-related Cancersmentioning

confidence: 93%

The enigmatic role of RUNX1 in female‐related cancers – current knowledge & future perspectives

Riggio

Blyth

2017

The FEBS Journal

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Historically associated with the aetiology of human leukaemia, the runtrelated transcription factor 1 (RUNX1) gene has in recent years reared its head in an assortment of epithelial cancers. This review discusses the state-of-the-art knowledge of the enigmatic role played by RUNX1 in female-related cancers of the breast, the uterus and the ovary. The weight of evidence accumulated so far is indicative of a very context-dependent role, as either an oncogene or a tumour suppressor. This is corroborated by high-throughput sequencing endeavours which report different genetic alterations affecting the gene, including amplification, deep deletion and mutations. Herein, we attempt to dissect that contextual role by firstly giving an overview of what is currently known about RUNX1 function in these specific tumour types, and secondly by delving into connections between this transcription factor and the physiology of these female tissues. In doing so, RUNX1 emerges not only as a gene involved in female sex development but also as a crucial mediator of female hormone signalling. In view of RUNX1 now being listed as a driver gene, we believe that greater knowledge of the mechanisms underlying its functional dualism in epithelial cancers is worthy of further investigation.

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“…The runt-related transcription factor 3 gene ( RUNX3 ) has been shown to be a tumour suppressor in a variety of cancers. Guo et al recently reported that the inactivation of the RUNX3 gene by promoter hypermethylation plays a role in the malignant transformation of ovarian endometriosis and is closely related to estrogen metabolism ( 117 ). The tumour suppressor gene, Ras-association domain family member 2 ( RASSF2 ), is inactivated by promoter hypermethylation in many types of cancer ( 118 – 120 ).…”

Section: Malignant Transformation Of Endometriosismentioning

confidence: 99%

DNA methylation in endometriosis (Review)

Koukoura

Sifakis

Spandidos

2016

Molecular Medicine Reports

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Endometriosis is defined by the presence and growth of functional endometrial tissue, outside the uterine cavity, primarily in the ovaries, pelvic peritoneum and rectovaginal septum. Although it is a benign disease, it presents with malignant characteristics, such as invasion to surrounding tissues, metastasis to distant locations and recurrence following treatment. Accumulating evidence suggests that various epigenetic aberrations may play an essential role in the pathogenesis of endometriosis. Aberrant DNA methylation represents a possible mechanism repsonsible for this disease, linking gene expression alterations observed in endometriosis with hormonal and environmental factors. Several lines of evidence indicate that endometriosis may partially be due to selective epigenetic deregulations influenced by extrinsic factors. Previous studies have shed light into the epigenetic component of endometriosis, reporting variations in the epigenetic patterns of genes known to be involved in the aberrant hormonal, immunologic and inflammatory status of endometriosis. Although recent studies, utilizing advanced molecular techniques, have allowed us to further elucidate the possible association of DNA methylation with altered gene expression, whether these molecular changes represent the cause or merely the consequence of the disease is a question which remains to be answered. This review provides an overview of the current literature on the role of DNA methylation in the pathophysiology and malignant evolution of endometriosis. We also provide insight into the mechanisms through which DNA methylation-modifying agents may be the next step in the research of the pharmaceutical treatment of endometriosis.

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RUNX3 is inactivated by promoter hypermethylation in malignant transformation of ovarian endometriosis

Cited by 21 publications

References 34 publications

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

The enigmatic role of RUNX1 in female‐related cancers – current knowledge & future perspectives

DNA methylation in endometriosis (Review)

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