Opposite prognostic roles of HIF1β and HIF2β expressions in bone metastatic clear cell renal cell cancer

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1 beta/HIF2 beta and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2 beta was lower in mRCC both at mRNA and protein levels (p/mRNA/ = 0.011, p/protein/ = 0.001) while HIF1 beta was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2 beta and high HIF1 beta as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2 alpha protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1 beta gene expression in primary RCC as an adverse (p = 0.07), whereas higher HIF2 beta and VEGFR2 expressions as favorable prognostic factors. HIF1 beta/HIF2 beta-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1 beta and HIF2 beta as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2 beta protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1 beta, increased HIF2 beta expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC.