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Opposite prognostic roles of HIF1? and HIF2? expressions in bone metastatic clear cell renal cell cancer.

ABSTRACT: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1?/HIF2? and their selected target genes in primary tumors and corresponding bone metastases.Expression of HIF2? was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1? was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2? and high HIF1? 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? protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1? gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2? and VEGFR2 expressions as favorable prognostic factors. HIF1?/HIF2?-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort.Expressions of HIF1? and HIF2? 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.We identified HIF2? protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1?, increased HIF2? expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC.

SUBMITTER: Szendroi A

PROVIDER: S-EPMC5173118 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Szendrői Attila A Szász A Marcell AM Kardos Magdolna M Tőkés Anna-Mária AM Idan Roni R Szűcs Miklós M Kulka Janina J Nyirády Péter P Szendrői Miklós M Szállási Zoltán Z Győrffy Balázs B Tímár József J

Oncotarget 20160701 27

<h4>Background</h4>Prognostic 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.<h4>Results</h4>Expression 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 ...[more]

PMID: 27244898

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Project description:Background: Kidney renal clear cell carcinoma (KIRC) is the malignancy originated from the renal epithelium, with a high rate of distant metastasis. Aberrant alternative splicing (AS) of pre-mRNA are widely reported to be involved in the tumorigenesis and metastasis of multiple cancers. The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC. Methods: RNA-seq of 537 KIRC samples downloaded from the TCGA database and ASEs data from the TCGASpliceSeq database were used to identify ASEs in patients with KIRC. The univariate and Lasso regression analysis were used to screen the most significant overall survival-related ASEs (OS-SEs). Based on those, the OS-SEs model was proposed. The interaction network of OS-SEs and splicing factors (SFs) with absolute value of correlation coefficient value >0.750 was constructed by Pearson correlation analysis. The OS-SEs significantly related to distant metastasis and clinical stage were identified by non-parametric test, and those were also integrated into co-expression analysis with prognosis-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways identified by Gene Set Variation Analysis (GSVA). ASEs with significance were selected for multiple online database validation. Results: A total of prognostic 6,081 overall survival-related ASEs (OS-SEs) were identified by univariate Cox regression analysis and a prediction model was constructed based on 5 OS-SEs screened by Lasso regression with the Area Under Curve of 0.788. Its risk score was also illustrated to be an independent predictor, which the good reliability of the model. Among 390 identified candidate SFs, DExD-Box Helicase 39B (DDX39B) was significantly correlated with OS and metastasis. After external database validation, Retained Intron of Ras Homolog Family Member T2 (RHOT2) and T-Cell Immune Regulator 1 (TCIRG1) were identified. In the co-expression analysis, overlapped co-expression signal pathways for RHOT2 and TCIRG1 were sphingolipid metabolism and N-glycan biosynthesis. Conclusions: Based on the results of comprehensive bioinformatic analysis, we proposed that aberrant DDX39B regulated RHOT2-32938-RI and TCIRG1-17288-RI might be associated with the tumorigenesis, metastasis, and poor prognosis of KIRC via sphingolipid metabolism or N-glycan biosynthesis pathway.

Dataset Information

Opposite prognostic roles of HIF1? and HIF2? expressions in bone metastatic clear cell renal cell cancer.

Publications

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

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