Hypoxia inducible factor-1α correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma

Dorević, Gordana; Matušan-Ilijaš, Koviljka; Babarović, Emina; Hadžisejdić, Ita; Grahovac, Maja; Grahovac, Blaženka; Jonjić, Nives

doi:10.1186/1756-9966-28-40

Cited by 54 publications

(29 citation statements)

References 26 publications

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“…Several studies found VEGF-A overexpression as adverse prognostic marker [17, 24, 25], while others opted for VEGFR1 [17]. In summary, data are either controversial or missing on various HIFs and on HIF-regulated gene expressions as prognostic markers in ccRCC, especially regarding bone metastatic diseases.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…On the other hand, previous studies have shown that HIF-1α expression is an adverse prognostic marker in ccRCC. 8,10,19,23,30 This is of particular interest since inactivation of the VHL tumor suppressor gene results in stabilization of the HIF-1α subunit. 16 Furthermore, HIF-1α is thought to downregulate the mTOR pathway independent of a hypoxic microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Immunoexpression Status and Prognostic Value of mTOR and Hypoxia-Induced Pathway Members in Primary and Metastatic Clear Cell Renal Cell Carcinomas

Schultz¹,

Chaux²,

Albadine³

et al. 2011

American Journal of Surgical Pathology

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The need for effective targeted therapies for renal cell carcinomas (RCC) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC) tissue microarrays were constructed from 135 primary and 41 metastatic ccRCC. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCC compared to benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4EBP1 were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared to benign tissues (P<0.001). c-MYC levels were higher in metastatic ccRCC (P<0.0001) and incremental p27 levels were observed in benign, primary ccRCC, and metastatic ccRCC (P<0.0001). HIF-1α levels were significantly higher in primary and metastatic ccRCC compared to benign tissues (P<0.0001). In primary ccRCC, levels of all mTOR and hypoxia-induced pathway members were significantly associated with pT stage (P≤0.036), p27 levels with Fuhrman grade (P=0.031), and 4EBP1, p27, and HIF-1α levels with tumor size (P≤0.025). Tumor size, HIF-1α and phos-S6 levels were associated with disease-specific survival (P≤0.032) and tumor progression (P≤0.043). In conclusion, both mTOR and hypoxia-induced pathways were activated in primary and metastatic ccRCC. PTEN loss seems to be an early event during tumorigenesis. Tumor size, HIF-1α and phos-S6 expression were found to be independent predictors of both DSS and tumor progression in primary ccRCC.

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“…Although the definition of high HIF1α expression varied among studies, on average HIF1α protein was detected in 70% (range 17% to 97%) of ccRCC specimens. In a number of studies, HIF1α expression was associated with an inferior survival [55, 56, 61, 63]. Schultz et al [61] showed that HIF1α levels were significantly higher in primary and metastatic ccRCCs compared with benign tissues (P<0.0001), and that tumor size and HIF1α expression were independent predictors of both reduced disease free survival and tumor progression in primary ccRCC.…”

Section: Reviewmentioning

confidence: 99%

The role of HIF1α in renal cell carcinoma tumorigenesis

Gudas

Minton

et al. 2014

J Mol Med

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The transcription factor HIF1α is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1α was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2α in ccRCC, but a tumor suppressor role for HIF1α [1], leading to uncertainty as to the precise roles of the different HIF transcription factors in this disease. Using evidence available from studies with human ccRCC cell lines, mouse xenografts, murine models of ccRCC, and human ccRCC specimens, we evaluate the roles of HIF1α and HIF2α in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1α in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1α and HIF2α is incomplete and that further research is required to determine the diverse roles of HIF1α and HIF2α in ccRCC.

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Hypoxia inducible factor-1α correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma

Cited by 54 publications

References 26 publications

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

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

Immunoexpression Status and Prognostic Value of mTOR and Hypoxia-Induced Pathway Members in Primary and Metastatic Clear Cell Renal Cell Carcinomas

The role of HIF1α in renal cell carcinoma tumorigenesis

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