DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma

Slater, Amy Amelia; Alokail, Majed S.; Gentle, Dean; Yao, Masahiro; Kovács, Gyula; Maher, Eamonn R.; Latif, Farida

doi:10.4161/epi.23817

Cited by 43 publications

(39 citation statements)

References 27 publications

(25 reference statements)

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“…We had similar finding here such that none of the patients with chromophobe RCC had distant metastasis at the time of diagnosis. Genetic and epigenetic differences of different subtypes of renal cell carcinoma were also previously demonstrated [38]. In accordance we here observed that adjusted level of CGRP was not decreased in chromophobe RCC while it was markedly diminished in clear and papillary RCC demonstrating possible protective effects of CGRP.…”

Section: Discussionsupporting

confidence: 78%

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

Erin

Ipekci

Akkaya

et al. 2016

Cancer Microenvironment

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Calcitonin Gene-related Peptide (CGRP), Vasoactive Intestinal Peptide (VIP) and Substance P (SP) are sensory neuropeptides which may alter cancer growth through modulation of chronic inflammation. We recently reported that SP suppresses breast cancer growth and metastasis through neuroimmune modulation. These neuropeptides are hydrolyzed by Neprilysin (NEP) to bioactive fragments. Decreased activity of NEP was reported in clear cell and chromophobe type renal cell carcinoma (RCC). It is however not known how the levels of neuropeptides hydrolyzed with NEP changes in RCC. Decrease activity of SP and CGRP containing sensory nerve endings was previously reported to increase cancer metastasis in animal models. It is however not known how peptidergic nerve endings are altered in RCC. Hence we here evaluated the levels of neuronal and non-neuronal neuropeptides and NEP activity in RCC including papillary type as well as neighboring uninvolved kidney. A cross-sectional study was conducted in 57 patients undergoing radical nephrectomy and diagnosed with RCC. NEP activity, levels and expression were determined using flourogenic substrate, western blot and qPCR respectively in freshly-frozen tissues. Immunohistochemical analyses were also performed.Neuronal and non-neuronal levels of CGRP, SP and VIP levels were determined using two-step acetic acid extraction. Levels and activity of NEP were markedly decreased in RCC regardless of subtype. Similar levels of VIP were detected in first and second extractions. VIP levels were higher in clear cell and papillary RCC compared to nearby kidney tissue. VIP levels of neighboring kidney tissue of papillary type RCC was significantly lower compared to kidney samples from clear cell RCC. CGRP levels were higher in second extraction. Similar to VIP levels, CGRP levels of neighboring kidney tissue from clear cell and chromophobe type RCC was significantly lower compared to corresponding tumor samples, an effect observed in the second extraction. VIP and CGRP levels of nearby kidney tissue varied subtype dependently demonstrating that different subtypes of RCC alter their local environment differently. Furthermore NEP-induce hydrolysis of VIP creates selective VPAC-1 receptor agonist which has anti-proliferative and anti-inflammatory effects. Hence loss of NEP activity may prevent antitumoral effects of VIP on RCC.

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Section: Discussionsupporting

confidence: 78%

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

Erin

Ipekci

Akkaya

et al. 2016

Cancer Microenvironment

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“…The results of the present study demonstrated that EN2 gene promoter was hyper-methylated in 12/40 primary cc-RCC tissues and all tested cc-RCC cell lines, whereas none of the 40 adjacent non-malignant tissues revealed hyper-methylation. The results of the present study were similar to the findings reported by Slater et al (38). Slater et al observed that EN2 was hyper-methylated in chromophobe RCC (6/20) but not renal oncocytoma (0/21).…”

Section: No Of Patients Withsupporting

confidence: 82%

“…Slater et al observed that EN2 was hyper-methylated in chromophobe RCC (6/20) but not renal oncocytoma (0/21). However, they did not investigate the function of EN2 methylation in chromophobe RCC (38). In the present study, the analysis of association between EN2 methylation and clinicopathological parameters indicated that EN2 methylation was significantly associated with increased malignant behavior in cc-RCC.…”

Section: No Of Patients Withmentioning

confidence: 83%

Engrailed‑2 promoter hyper‑methylation is associated with its downregulation in clear cell renal cell carcinoma

Lai

et al. 2017

Oncol Lett

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Abstract. In a previous study by the present authors, it was identified that the expression of engrailed-2 (EN2) gene was downregulated in clear cell renal cell carcinoma (cc-RCC). The aim of the present study was to determine whether aberrant methylation was the mechanism underlying the silencing of EN2 gene in cc-RCC. A total of forty paired cc-RCC tissues, four cc-RCC cell lines and one normal human proximal tubule epithelial cell line were evaluated for EN2 gene methylation status using methylation-specific polymerase chain reaction (PCR). Following treatment with 5-Aza-dc, reverse transcription-quantitative PCR and western blot analysis were performed to examine the expression of EN2. Furthermore, cell proliferation, apoptosis and invasion assays were conducted to analyze the inhibitory effects of EN2 re-expression in 786-O cells. The results of the present study demonstrated that hyper-methylation of EN2 was identified in 12/40 cc-RCC tissues and all cc-RCC cell lines. The methylation status of the EN2 gene was revealed to be associated with histological grade and tumor size in cc-RCC. Following 5-Aza-dc treatment, demethylation of the EN2 gene was identified in 786-O cells, in conjunction with EN2 re-expression. Furthermore, re-activation of the EN2 gene markedly inhibited the proliferative and invasive capacities of cc-RCC. The results of the present study demonstrated that the EN2 gene promoter was hyper-methylated in cc-RCC, which may underlie the silencing of the EN2 gene in cc-RCC.

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“…These investigations differentiate hormone receptor-positive breast cancers from hormone receptor-negative cases using DNA methylation profiles [49,77,[83][84][85]. The majority of genome wide DNA methylation studies have found that ER+PR+tumours have higher levels of DNA methylation compared with ER−PR− tumours [77,82,85,86].…”

Section: Dna Methylation and Breast Cancermentioning

confidence: 99%

DNA Methylation

Alokail¹,

Alenad²

2015

A Concise Review of Molecular Pathology of Breast Cancer

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DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma

Cited by 43 publications

References 27 publications

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma

Engrailed‑2 promoter hyper‑methylation is associated with its downregulation in clear cell renal cell carcinoma

DNA Methylation

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