Alterations of the WNT7A Gene in Clear Cell Renal Cell Carcinomas

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.

Expression of WNT genes in cervical cancer-derived cells: Implication of WNT7A in cell proliferation and migration

“…Our research group also previously reported that restoration of WNT7A expression in leukemia-derived lymphoblasts inhibits cell proliferation [20]. In our study, we were able to determine that loss of WNT7A expression in HeLa and SiHa cells was due to hypermethylation; this observation has also been reported in CCRCC [27] and in human NSCLC [43]. In contrast, CpG methylation of the WNT7A gene was not detected in pancreatic endocrine tumors [44].…”

“…To our knowledge, there are no previous reports regarding WNT7A expression in this pathology. However, there are some evidences in other cancer cell models; for example, it has been determined that the WNT7A gene is inactivated in clear cell renal-cell carcinomas [27]. Additionally, it has been reported that WNT7A expression is frequently reduced or absent in lung cancers when compared with normal lung and mortal, short-term bronchial epithelial cultures [32].…”

“…Regarding this point, it has been reported that the WNT7A gene possesses a tumor suppression function by means of Colony formation (CF) and cell proliferation assays in Clear cell renal cell carcinomas (CCRCC) [27], and that restoration of WNT7A expression reverses Non-small cell lung cancer (NSCLC) cellular transformation through FZD 9-mediated growth inhibition and promotion of cell differentiation [19]. Our research group also previously reported that restoration of WNT7A expression in leukemia-derived lymphoblasts inhibits cell proliferation [20].…”

“…To determine whether WNT7A is reduced in CC-derived cells due to aberrant hypermethylation, as previously described in lung and kidney cancer [27,28], the methylation state of 3 CpG islands within the WNT7A promoter and gene (from À1200 to þ600 pb) in HaCaT, HeLa, and SiHa cells was assessed. As shown in Fig.…”

Overexpression of Wnt7α protein predicts poor survival in patients with colorectal carcinoma

“…Researchers have revealed that WNT members function differently in carcinogenesis; for example, Wnt2 is reported to be a tumor promoter [18], whereas Wnt5α has been shown to possess antitumor features [15]. Previous studies have identified the role of Wnt7α in several other cancers; [30][31][32], clear cell renal cell carcinoma (RCC) [33], and acute lymphoblastic leukemia (ALL) [34]. However, in ovarian cancer patients, Wnt7α shows higher expression in clinical samples of malignant ovarian tumors than in normal ovaries and benign tumors, and also, high Wnt7α expression is correlated with poor overall patient survival [21].…”