Abstract
Renal cell carcinoma (RCC) is a malignancy with poor prognosis. WNT/β-catenin signaling dysregulation, especially β-catenin overactivation and WNT antagonist silencing, is associated with RCC carcinogenesis and progression. However, the role of WNT ligands in RCC has not yet been determined. We screened 19 WNT ligands from normal kidney and RCC cell lines and tissues and found that WNT10A was significantly increased in RCC cell lines and tissues as compared to that in normal controls. The clinical significance of increase in WNT10A was evaluated by performing an immunohistochemical association study in a 19-year follow-up cohort comprising 284 RCC and 267 benign renal disease (BRD) patients. The results of this study showed that WNT10A was dramatically upregulated in RCC tissues as compared to that in BRD tissues. This result suggests that WNT10A, nuclear β-catenin, and nuclear cyclin D1 act as independent risk factors for RCC carcinogenesis and progression, with accumulative risk effects. Molecular validation of cell line models with gain- or loss-of-function designs showed that forced WNT10A expression induced RCC cell proliferation and aggressiveness, including higher chemoresistance, cell migration, invasiveness, and cell transformation, due to the activation of β-catenin-dependent signaling. Conversely, WNT10A siRNA knockdown decreased cell proliferation and aggressiveness of RCC cells. In conclusion, we showed that WNT10A acts as an autocrine oncogene both in RCC carcinogenesis and progression by activating WNT/β-catenin signaling.
Highlights
The worldwide incidence of renal cell carcinoma (RCC) is estimated to increase at an annual rate of approximately 2%; RCC accounts for approximately 1–3% of all adult malignancies
Our results showed that WNT10A expression was significantly higher in most RCC cell lines but not in the HK-2 cell line
Previous studies have shown that promoters of most WNT antagonistic genes are methylated or epigenetically silenced in RCC, which results in uninhibited WNT signaling during cancer initiation or progression [26]
Summary
The worldwide incidence of renal cell carcinoma (RCC) is estimated to increase at an annual rate of approximately 2%; RCC accounts for approximately 1–3% of all adult malignancies. In 2008, the incidence rate of RCC was 4/100,000, and its mortality rate was 1.6/100,000 worldwide. In Taiwan, the incidence rate of RCC was 3.2/100,000, and its mortality rate was 1.7/100,000 [1,2]. Nineteen members of WNT gene family, which encode secretory cysteinerich ligands, have been identified in human or mice genomes. These genes can be categorized into 2 classes based on the degree of transformation of mouse mammary epithelial cell line C57MG. The WNT1 series of genes have a higher ability to transform C57MG and include the WNT3, WNT3A, and WNT7A genes
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