Common reduction of the Raf kinase inhibitory protein in clear cell renal cell carcinoma
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Brianne Hill1,2,3, Jason De Melo1,2,3, Judy Yan1,2,3, Anil Kapoor3,4, Lizhi He1,2,3,5, Jean-Claude Cutz6, Xingchang Feng1,3,7, Nazihah Bakhtyar1,2,3, Damu Tang1,2,3
1 Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, Hamilton, Ontario, Canada
2 Father Sean O’Sullivan Research Institute, Hamilton, Ontario, Canada
3 The Hamilton Center for Kidney Research, St. Joseph’s Hospital, Hamilton, Ontario, Canada
4 Division of Urology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
5 Department of Biological Chemistry and Molecular Pharmacology (BCMP), Harvard Medical School, Boston, MA, USA
6 Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
7 College of Veterinary Medicine, Northeast Agricultural University, Harbin, China 150030
Damu Tang e-mail: [email protected]
Running title: RKIP suppresses ccRCC tumorigenesis
Key words: RKIP, Raf, ERK, ccRCC, and kidney cancer
Received: October 30, 2013 Accepted: April 21, 2014 Published: April 24, 2014
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.
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