Abstract
Retinoblastoma protein-interacting zinc finger gene 1(RIZ1) functions as a tumor suppressor. Hypermethylation-mediated RIZ1 silencing has been reported in several cancers, but not in renal cell carcinoma (RCC) yet. We examined the RIZ1 expression and methylation in a panel of RCC cell lines and 50 primary tumors using semiquantitative/quantitative polymerase chain reaction (PCR), methylation specific PCR, and bisulfite sequencing genomic. We also explored the relationship between methylation status of RIZ1 and clinicopathological features in RCC patients. RIZ1 expression was down-regulated or lost in OS-RC-2, 769-P, Caki-1, 786-O and A498 RCC cell lines. Restored expression of RIZ1 was detected after addition of 5-aza-2'-deoxycytidine with/without trichostatin A, suggesting that DNA methylation directly mediates its silencing. The RIZ1 expression was significantly reduced in RCCs compared to adjacent non-malignant renal samples (P<0.001). Aberrant methylation was detected in 15 of 50 (30%) RCCs and in 2 of 28 (7%) adjacent non- malignant renal samples (P=0.02). No statistically significant correlation between methylated and unmethylated cases with regard to age, gender, pathological stage and grade was observed. RIZ1 expression is down-regulated in human RCC, and this down-regulation is associated with methylation. RIZ1 methylation may play a role in renal carcinogenesis.
Highlights
Renal cell carcinoma (RCC) accounts for more than 90% of all kidney malignancies, with the highest incidence occurring in Western countries
We examined the expression of RIZ1 in 5 renal cell carcinoma (RCC) cell lines and the immortalized human normal embryonic kidney cell line HEK293 using RT-polymerase chain reaction (PCR)
High density of methylated CpG sites were found in 769-P cell line (Figure 2A). These results suggest RIZ1 gene expression level is closely correlated with its promoter methylation status inversely
Summary
Renal cell carcinoma (RCC) accounts for more than 90% of all kidney malignancies, with the highest incidence occurring in Western countries. Aberrant methylation represents an early event in cancer formation (Miyamoto et al, 2005) Together, these results suggest a promising value of DNA methylation for early diagnosis and prognosis (de Martino et al, 2012; Raja et al, 2012; Hauser et al, 2013; Haroun et al, 2014). A wealth of genes have been described as methylation targets in RCC, such as DAPK, SPINT2, APC, RASSF1A, VHL, γ-catenin, P16 and CDH1 (Zhang et al, 2007; Zhang et al, 2010; Hoffman et al, 2011; Zhang et al, 2014). Most of these TSGs represent a relative low rate of DNA methylation.
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