Abstract
WNT7A (wingless-type MMTV integration site family, member 7A) is a known tumor suppressor gene of non-small cell lung carcinomas (NSCLC) and is frequently inactivated due to CpG-island hypermethylation in human cancers. The members of WNT family are involved in cell signaling and play crucial roles in cancer development. In the present work hypermethylation of the WNT7A gene was detected in 66% (29/44) of analyzed clear cell renal cell carcinomas (RCCs) using methyl-specific PCR (MSP). Moreover, bisulfite sequencing confirmed intensive hypermethylation of the 5′-CpG island of the WNT7A gene. Methylation analysis revealed positive correlations between tumor stage, Fuhrman nuclear grade and WNT7A hypermethylation. Additionally, restoration of WNT7A gene expression in the A498 cell line by 5-aza-2′-deoxycytidine treatment confirmed a direct contribution of hypermethylation in silencing of the WNT7A gene. High frequency of loss of heterozygosity (LOH) was demonstrated on chromosome 3p25 in regions surrounding the WNT7A gene. The frequent down-regulation of WNT7A gene expression was detected in 88% (15/17) of clear cell RCCs. We have also shown that the WNT7A gene possesses tumor suppression function by colony-formation and cell proliferation assays in RCC cell lines. In summary, the WNT7A gene is inactivated by genetic/epigenetic alterations in clear cell RCC and demonstrates tumor suppressor properties.
Highlights
Renal cell carcinoma (RCC) is the most common type of kidney cancer, responsible for 3% of human malignancies [1]
DNA methylation of promoter regions was shown for RASSF1, FHIT, LRRC3B, VHL and other well-characterized tumor suppressor genes in clear cell RCCs [9,10,11,12]
To examine the presence of epigenetic alterations of the WNT7A gene in clear cell RCCs, the methylation status of the 59CpG island of the WNT7A gene was first assessed by methyl-specific PCR (MSP)
Summary
Renal cell carcinoma (RCC) is the most common type of kidney cancer, responsible for 3% of human malignancies [1]. Clear cell RCC accounts for 70–75% of RCC and is distinguished by a set of genetic and epigenetic abnormalities [2]. It was shown that abnormalities of human chromosome 3 significantly contributed to clear cell RCCs development. Arai et al identified chromosome 3 as one of the most affected by genetic/epigenetic alterations in clear cell RCCs [7,8]. DNA methylation of promoter regions was shown for RASSF1, FHIT, LRRC3B, VHL and other well-characterized tumor suppressor genes in clear cell RCCs [9,10,11,12]
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