Opposite prognostic roles of HIF1α and HIF2α expressions in bone metastatic clear cell renal cell cancer

Abstract

BACKGROUNDPrognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1α/HIF2α and their selected target genes in primary tumors and corresponding bone metastases.RESULTSExpression of HIF2α was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1α was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2α and high HIF1α 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 HIF2α protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1α gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2α and VEGFR2 expressions as favorable prognostic factors. HIF1α/HIF2α-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort.PATIENTS AND METHODSExpressions of HIF1α and HIF2α 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.CONCLUSIONSWe identified HIF2α protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1α, increased HIF2α expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC.

Survival prediction of kidney renal papillary cell carcinoma by comprehensive LncRNA characterization

“…Currently, several biomarkers for KIRC that have been detected include von Hippel-Lindau (VHL) [ 8 – 11 ], vascular endothelial growth factor (VEGF) [ 12 – 15 ], carbonic anhydrase IX (CAIX) [ 16 – 18 ], and hypoxia-inducible factor 1 alpha/2 alpha (HIF1a/2a) mutations [ 19 – 21 ], some of which were able to forecast the medical effectiveness and outcomes. Despite that, there have been scarce studies into the molecular biomarkers of KIRP for the prediction of therapeutic efficacy and prognostication.…”

Prognostic Role of Hypoxia-Inducible Factor-2α Tumor Cell Expression in Cancer Patients: A Meta-Analysis

“…A total of 38 from the selected 49 studies investigated the association between HIF-2α and OS. All the necessary information to estimate the HR could not be obtained from two papers and were therefore not included in the analysis (Table S1 in Supplementary Material) ( 21 , 23 , 24 , 26 – 31 , 33 – 35 , 37 – 39 , 41 – 43 , 45 , 46 , 48 , 49 , 51 , 52 , 54 – 57 , 59 , 60 , 62 – 69 ). Based on these studies, high HIF-2α expression was statistically significantly associated with a decreased OS (HR = 1.69, 95% CI 1.39–2.06, p < 0.0001, Figure 3 ).…”

“…We found that the pooled HR for MFS was 2.67 (95% CI 1.32–5.38, p = 0.0061), indicating that HIF2α expression is a negative prognostic factor for MFS in patients with prostate and salivary gland cancer (Figure 7 ). In kidney cancer, one paper reported an inverse correlation between HIF-2α positivity and MFS (HR = 0.08, 95% CI 0.03–0.27, p < 0.001) ( 23 ).…”

The Clinicopathologic and Prognostic Value of Hypoxia-Inducible Factor-2α in Cancer Patients: A Systematic Review and Meta-Analysis

“…Many lines of evidence suggest that the expression level of HIF2a was enhanced and predicted poor survival in a variety of cancers, (32). Conversely, some studies have indicated that HIF2a have a significant impact on the development of tumors, and increased HIF2a expression could be a favorable prognostic factor in RCC (43) and HCC (21). Moreover, clinicopathologic significance of HIF2a in cancer patients remains inconclusive.…”