Renal cell carcinoma and the WNT/β-catenin pathway

The highly conserved WNT pathway is involved in the transduction of signals from the cell surface to the nucleus, and it is known to play a key role in embryonic development, adult tissue maintenance and tumourigenesis (Klaus & Birchmeier, 2008). However, the exact role of the WNT family in the development of renal cell carcinoma (RCC) is not fully known. A paper by Hsu et al. (2012) has now suggested that WNT10A is associated with RCC through the activation of β-catenin signalling.

Using RT-PCR, the authors first measured the expression of 19 WNT genes in five human RCC cell lines (786-OCaki-1RCC-1A498 and ACHN) and a normal human kidney cell line (HK-2). The results showed that WNT10A expression was significantly higher in most of the RCC cell lines, but not in the HK-2 cells. A similar finding was obtained using human kidney specimens, showing that WNT10A expression was significantly higher in most RCC tumours when compared to normal kidney tissue, as shown by RT-PCR and immunohistochemical analysis. WNT10A was also seen to have a strong cytoplasmic/membranous staining pattern using immunohistochemistry. Canonical WNT signalling is known to regulate β-catenin, and accordingly there were increased levels of β-catenin in both the cytoplasm and nucleus of RCC cells. Nuclear expression of the c-myc and cyclin D1 genes (which are regulated by β-catenin) were also significantly increased in these RCC tumours.

siRNA knockdown of WNT10A in RCC-1 and Caki-1 cells reduced the levels of nuclear β-catenin, cyclin D1 and c-myc. Conversely, increased expression of WNT10A in HK-2, 786-O and A498 cells upregulated the expression of nuclear β-catenin, cyclin D1 and c-myc, and this effect was reversed upon β-catenin siRNA knockdown. The effect of WNT10A on β-catenin signalling was also confirmed using a luciferase reporter assay in Caki-1 and 786-O cells.

Functionally, increased expression of WNT10A promoted the proliferation of HK-2, 786-O and A498 cells in vitro. Using 786-O cells in a wound-healing, transwell and soft agar assay, there was also greater cell migration, invasion and colony formation with increased levels of WNT10A. These tumourigenic processes were reduced by siRNA knockdown of β-catenin.

Finally, using data from a 19-year follow-up study of 284 RCC patient tumours, it could be seen that higher levels of WNT10A, nuclear β-catenin and nuclear cyclin D1 were risk factors for renal tumourigenesis. Moreover, RCC patients with a combination of these factors had a poor prognosis. Consequently, could WNT10A act as a biomarker and a potential therapeutic target for RCC? Additionally, could the WNT/β-catenin pathway also play a role in the development of kidney cancer in BHD syndrome?

 

  • Hsu RJ, Ho JY, Cha TL, Yu DS, Wu CL, Huang WP, Chu P, Chen YH, Chen JT, & Yu CP (2012). WNT10A Plays an Oncogenic Role in Renal Cell Carcinoma by Activating WNT/β-catenin Pathway. PloS one, 7 (10) PMID: 23094073
  • Klaus A, & Birchmeier W (2008). Wnt signalling and its impact on development and cancer. Nature reviews. Cancer, 8 (5), 387-98 PMID: 18432252

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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