Oxidative stress and DNA hypermethylation status in renal cell carcinoma arising in patients on dialysis

Abstract

Renal cell carcinoma (RCC) is more frequently observed in patients on dialysis than in patients with normal renal function. However, the mechanism underlying carcinogenesis in RCC patients on dialysis is still unclear. We hypothesized that oxidative stress affects patients on dialysis and generates new neoplasms, and therefore analysed the correlation between the influences of various markers of oxidative stress and carcinogenesis in those patients. We evaluated the immunohistochemical expression of oxidative stress markers, such as iNOS, 8-OHdG, and COX-2 in 42 cases on dialysis and 51 cases with normal renal function as a control. The methylation status of p16INK4a, p14ARF, VHL, and RASSF1A was analysed together with clinicopathological factors. Histologically, the papillary type was observed more frequently in dialysis RCC than in sporadic RCC. Immunohistochemically, overexpression of iNOS (p < 0.0001) and COX-2 (p = 0.0002) was more frequently observed in dialysis RCC. Furthermore, the 8-OHdG labelling index was significantly higher in dialysis RCC than in sporadic RCC. Hypermethylation of p16INK4a was more frequently found in dialysis RCC (p < 0.05). However, no significant correlations between oxidative stress markers and DNA hypermethylation status were observed. The overexpression of iNOS, COX-2, and 8-OHdG in dialysis RCC suggests that patients on dialysis are affected by oxidative stress and that this effect plays an important role in the genesis of dialysis RCC.

Regulation of RASSF1A in nasopharyngeal cells and its response to UV irradiation

“…Oxidative stress could generate ROS leading to various forms of DNA damage, including base change, DNA strand break, and cross-linking (Ghosh and Mitchell, 1999). Oxidative stress could also hypermethylate the promoter of RASSF1A gene, such as in renal cell carcinoma (Hori et al, 2007) and skin lesions (Sathyanarayana et al, 2007). In the present study, UV irradiation was found to significantly reduce RASSF1A promoter function and hence endogenous RASSF1A transcript.…”

Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism

“…However, excessive levels of ROS produced by pro-oxidants generated either endogenously through cellular metabolism or through various exogenous sources cause oxidative injury to kidney cells leading to kidney diseases. This is further supported by the evidence of higher levels of oxidative stress in RCC patients (Hori et al, 2007;Ganesamoni et al, 2012), in renal injury related to obesity (Quigley et al, 2009), and in an experimental model of renal carcinogenesis (Gago-Dominguez et al, 2002). Increased oxidative stress and activation of oxidative stress-induced DNA damage repair pathway in kidney cells of diabetic patients have been reported (Forbes et al, 2008;Kashihara et al, 2010;Caramori et al, 2015).…”

DNA methylation profiling in cell models of diabetic nephropathy

“…7,8 There is increasing evidence from various studies to suggest that epigenetic factors may be implicated in DN. [9][10][11][12][13][14][15] We have demonstrated differential expression in several plausible biological candidate genes for DN in various cell models of disease and also renal biopsies from individuals with DN, and have demonstrated upregulation of several genes involved in EMT. [16][17][18][19][20] The objectives of the present study were to perform quantitative DNA methylation profiling in 5' promoter regions of candidate genes (n = 192) previously identified by us to be differentially expressed in cells models of DN or renal biopsies from diabetic individuals with nephropathy to compare DNA methylation signatures in unstimulated human mesangial cells (HMCs) with proximal tubular epithelial cells (PTCs) and assess patterns of DNA methylation in HMCs and PTCs before and after exposure to various stimuli (high extracellular glucose, TGFβ1, CTGF, a combination of TGFβ1 and CTGF, or platelet-derived growth factor (PDGF)).…”