Common reduction of the Raf kinase inhibitory protein in clear cell renal cell carcinoma.

Brianne Hill,Xingchang Feng,Lizhi He,Anil Kapoor,Damu Tang,Jean-Claude Cutz,Jason De Melo,Judy Yan,Nazihah Bakhtyar

doi:10.18632/oncotarget.1558

Abstract

Despite the recent progress in our understanding of clear cell renal cell carcinomas (ccRCCs), the etiology of ccRCC remains unclear. We reported here a prevailing reduction of the raf kinase inhibitory protein (RKIP) in ccRCC. In our examination of more than 600 ccRCC patients by western blot and immunohistochemistry, RKIP was significantly reduced in 80% of tumors. Inhibition of RKIP transcription in ccRCC occurs to greater levels than VHL transcription based on the quantification analysis of their transcripts in six large datasets of DNA microarray available in Oncomine™ with the median rank of suppression being 582 and 2343 for RKIP and VHL, respectively. Collectively, the magnitude of RKIP reduction and the levels of its downregulation match those of VHL. Furthermore, RKIP displays tumor suppressing activity in ccRCC. While modulation of RKIP expression did not affect the proliferation of A498 and 786-0 ccRCC cells and neither their ability to form xenograft tumors in NOD/SCID mice, ectopic expression or knockdown of RKIP inhibited or enhanced A498 and 786-0 ccRCC cell invasion, respectively. This was associated with robust changes in vimentin expression, a marker of EMT. Taken together, we demonstrate here that downregulation of RKIP occurs frequently at a rate that reaches that of VHL, suggesting RKIP being a critical tumor suppressor for ccRCC. This is consistent with RKIP being a tumor suppressor for other cancers.

Highlights

Renal cell carcinoma (RCC) accounts for 85% of kidney cancer cases
One spot with a molecular weight of approximately 20 kDa and pI 7.42 was commonly detected in adjacent non-tumor kidney (ANK), which was consistently reduced in the respective clear cell renal cell carcinomas (ccRCCs) (Fig. 1A)
Clear cell renal cell carcinoma is commonly associated with upregulation/activation of VEGF, PDGF-β, and TGF-α [45,46]

Summary

Introduction

Renal cell carcinoma (RCC) accounts for 85% of kidney cancer cases. Clear cell RCC is the most prevalent, the most aggressive [3], and the most common cause of kidney cancer-associated deaths [4]. Loss of VHL is a critical event for ccRCC tumorigenesis. Accumulating evidence clearly demonstrates VHL being a critical tumor suppressor of ccRCC. Patients with VHL deficiency develop ccRCCs that are often preceded by pre-neoplastic renal cysts [9] and mice deficient in VHL in the proximal tubule epithelium only develop low levels of renal cysts [10], demonstrating the requirement of other oncogenic events

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Conclusion