Dataset Information

Expression of HIF‑α and their association with clinicopathological parameters in clinical renal cell carcinoma.

ABSTRACT:

Objectives

This study aimed to assess the cellular localization and expression levels of hypoxia-inducible factor (HIF) -α proteins (specifically HIF-1α, HIF-2α, and HIF-3α) that play a role in the hypoxia pathway and to determine their correlation with clinicopathological parameters and patient survival in renal cell carcinoma (RCC).

Materials and methods

Tissue microarray (TMA) with cores from 150 clear cell RCCs and 31 non-ccRCC samples. HIF-1α, HIF-2α, and HIF-3α antibodies were used for immunohistochemistry (IHC) of TMA to evaluate the cellular localization and expression levels of HIF-α proteins, specifically in relation to the hypoxia pathway.

Results

The expression levels of the HIF-α proteins were higher in the nucleus than in the cytoplasm. Furthermore, the nuclear expression levels of all HIF-α proteins were significantly higher in clear cell RCC (ccRCC) than in non-ccRCC. Cytoplasmic HIF-3α expression was also higher in ccRCC than in non-ccRCC, whereas cytoplasmic HIF-1α and HIF-2α expression levels were similar between the different RCC types. In ccRCC, nuclear HIF-1α expression levels correlated with both nuclear HIF-2α and HIF-3α levels, whereas cytoplasmic HIF-3α expression levels were associated with HIF-1α only.In non-ccRCC, there was a positive correlation observed between nuclear HIF-1α and HIF-3α expression, but no correlation was found with HIF-2α. In patients with ccRCC, the nuclear expressions of HIF-1α and HIF-3α was significantly associated with cancer-specific survival (CSS) in univariate analysis. This association was no longer evident in multivariate analysis. Notably, there was no correlation observed between nuclear HIF-2α expression and CSS in these patients. In contrast, cytoplasmic expression levels showed no association with CSS.

Conclusion

The expression levels of the three primary HIF-α proteins were found to be higher in the nucleus than in the cytoplasm. Furthermore, the results indicated that HIF-3α and HIF-1α expression levels were significant univariate factors associated with CSS in patients with clear cell RCC. These results highlight the critical role that HIF-3α and HIF-1α play in the hypoxia pathway.

SUBMITTER: Sitaram RT

PROVIDER: S-EPMC10989218 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Expression of HIF‑α and their association with clinicopathological parameters in clinical renal cell carcinoma.

Sitaram Raviprakash T RT Ljungberg Börje B

Upsala journal of medical sciences 20240321

<h4>Objectives</h4>This study aimed to assess the cellular localization and expression levels of hypoxia-inducible factor (HIF) -α proteins (specifically HIF-1α, HIF-2α, and HIF-3α) that play a role in the hypoxia pathway and to determine their correlation with clinicopathological parameters and patient survival in renal cell carcinoma (RCC).<h4>Materials and methods</h4>Tissue microarray (TMA) with cores from 150 clear cell RCCs and 31 non-ccRCC samples. HIF-1α, HIF-2α, and HIF-3α antibodies we ...[more]

PMID: 38571885

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Project description:Polo-like kinase 4 (PLK4) promotes tumorigenesis and is associated with the prognosis of several solid tumors, while its clinical role in patients with renal cell carcinoma (RCC) remains unidentified. The present study aimed to analyze the association of PLK4 with clinicopathological characteristics and long-term prognosis in patients with RCC. The present study detected PLK4 protein and mRNA expression using immunohistochemical and reverse transcription-quantitative PCR assays in 120 patients with RCC. Disease-free survival (DFS) and overall survival (OS) time were calculated based on a median follow-up duration of 6.9 years (range, 1.2-9.9 years). PLK4 protein expression was elevated in tumor tissues compared with adjacent tissues (P<0.001). Upregulation of PLK4 protein was associated with increased T stage (P=0.023), N stage (P=0.014) and TNM stage (P=0.007). Additionally, elevated tumor PLK4 protein expression exhibited an associating trend (without statistical significance) with reduced DFS rate (P=0.066) and was associated with decreased OS rate (P=0.036). However, univariate Cox's regression analysis indicated that high PLK4 protein expression (compared with low PLK4 protein expression) was associated with reduced OS rate (P=0.040) but not with PFS rate (P=0.070). Following adjustment by multivariate Cox's regression analysis, PLK4 protein expression was associated with neither DFS nor OS rate (both P>0.050). Additionally, PLK4 mRNA expression was further detected in some patients (for which fresh specimens frozen in liquid nitrogen were available) to validate the aforementioned observations, and the expression was elevated in tumor tissues compared with adjacent tissues. Furthermore, increased PLK4 mRNA expression was associated with tumor size ≥7 cm, high TNM stage and reduced DFS rate (all P<0.050). PLK4 possesses a certain clinical utility in monitoring the clinical stage of patients with RCC, while its prognostic value requires further validation.

Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1β) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1β, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

Dataset Information

Expression of HIF‑α and their association with clinicopathological parameters in clinical renal cell carcinoma.

Objectives

Materials and methods

Results

Conclusion

Publications

Expression of HIF‑α and their association with clinicopathological parameters in clinical renal cell carcinoma.

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