RKIP is commonly downregulated in clear cell renal cell carcinoma (ccRCC)

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by VHL mutations. More than 80% of ccRCCs are resulted from the loss of VHL, a remarkable prevalence that is unique for a tumor suppressor in ccRCC. Despite the required VHL loss, this event is not sufficient to result in ccRCC. The underlying mechanisms contributing to this insufficiency remain incompletely understood. Nonetheless, recent advances in whole genome sequencing have shed lights on these mechanisms. Whole genome sequencing a set of ccRCCs identified three tumor suppressors: BRCA1-associated protein 1 (BAP1), Polybromo-1 (PBRM1), and Set domain-containing 2 (SETD2) with their apparent mutation rates being 50% for PBRM1, 15% for BAP1, and 15% for SETD2. While concomitant mutations of VHL with these tumor suppressors will likely further the process of ccRCC pathogenesis, it is unlikely that these oncogenic events are inclusive. In supporting this possibility, we have recently reported reductions of the Raf kinase inhibitory protein (RKIP) in 80% of 600 ccRCCs examined. This is remarkable considering the tendency of ccRCC in predominantly using a single oncogenic factor, i.e. loss of the VHL tumor suppressor. RKIP inhibits Raf1-mediated activation of MEK/ERK, and also displays other tumor suppression activities. Downregulation of RKIP has been reported in many cancers particularly in those of metastasis, observations that support RKIP being a metastasis tumor suppressor. The current manuscript will provide insights regarding our ccRCC-related RKIP research, and suggest some future developments to delineate the contributions of RKIP to ccRCC tumorigenesis.