The Function of RKIP in the Tumourigenesis of Clear Cell Renal Cell Carcinoma

Abstract

<p>Despite clear cell renal cell carcinoma (ccRCC) being the most common and one of the most lethal forms of RCC, our understanding of ccRCC tumourigenesis remains limited. To identify factors contributing to ccRCC formation, we have found that raf kinase inhibitor protein (RKIP) is a candidate tumour suppressor of ccRCC. This is consistent with publications implicating that RKIP possesses tumour suppression functions in several human cancers. However, whether RKIP suppresses ccRCC tumorigenesis has yet to be determined. This thesis was therefore undertaken to examine the role of RKIP in the tumourigenesis of ccRCC as well as to gain knowledge about this understudied area of kidney cancer research. Upon examination of more than 600 patients with ccRCC in several independent patient cohorts, levels of RKIP protein are significantly reduced in more than 80% of ccRCC tumours in comparison to the adjacent non-tumour kidney or normal kidney tissues. This observed magnitude of RKIP reduction strongly suggests that RKIP is an important tumour suppressor of ccRCC. Supporting this concept is observations that ectopic expression of RKIP inhibited A498 and 786-O ccRCC cell invasion. Conversely, knockdown of RKIP in A498 and 786-O cells enhanced the invasion ability of those cells. Additionally, the progression of ccRCC into advanced tumour stages and tumour grades is correlated with a reduction in RKIP protein. This reduction of RKIP protein levels is more apparent in metastasized ccRCC tumours in which all tumours were negative for RKIP protein expression in comparison to the matched organ-confined tumours. To date there have been no reports investigating the role of RKIP in renal cell carcinoma, our results demonstrate a strong relationship between RKIP reduction and progression of this often fatal disease.</p>