Expression of HIF-2a in clear-cell renal cell carcinoma independently predicts overall survival

Gkagkalidis, Konstantinos; Kampantais, Spyridon; Dimitriadis, Georgios; Gourvas, Victoras; Καπουκρανίδου, Δωροθέα; Mironidou-Tzouveleki, Maria

doi:10.1007/s00795-020-00249-3

Cited by 13 publications

(11 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data indicated that cytoplasmic variables remain significant predictors of cancer specific survival, while neither nuclear HIF2α variables are retained [ 75 ]. Similar results were obtained in a recent study that revealed that ccRCC with high (cytoplasmic) HIF2α expression is associated with unfavorable disease [ 76 ].…”

Section: Hif1α and Hif2αsupporting

confidence: 90%

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Aljahdali

Zhang

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.

show abstract

Section: Hif1α and Hif2αsupporting

confidence: 90%

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Aljahdali

Zhang

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…19 Furthermore, our team has shown that HIF-2α immunohistochemistry expression adds further prognostic value for the survival of patients with ccRCC. 20 In the present study, HIF-2α mRNA levels in fresh frozen renal cancerous tissue compared with fresh frozen adjacent normal kidney tissue was inversely associated with Fuhrman grade. This confirms findings by Sandlung et al, who demonstrated that HIF-2α mRNA levels were inversely correlated with both Fuhrman grade and TNM stage in ccRCC.…”

Section: Discussionsupporting

confidence: 45%

Decreased prolyl hydroxylase 3 mRNA expression in oncocytomas compared with clear cell renal cell carcinoma

et al. 2020

Self Cite

View full text Add to dashboard Cite

Introduction: Hypoxia inducible factors (HIF) and prolyl hydroxylase domain (PHD) enzymes play a central role in tumor progression in clear cell renal cell carcinoma (ccRCC). However, there are currently no data regarding the behavior of this pathway (HIF/PHD) in a large number of benign renal tumors, the oncocytomas. The aim of the present study was to compare the expression levels of these factors between ccRCC and oncocytoma tumors. Material and methods: A total of 56 fresh frozen specimens from patients with ccRCC and 14 oncocytoma specimens were analyzed via reverse transcription-quantitative polymerase chain reaction in order to assess the expression levels of HIF-1α, HIF-2α, PHD1, PHD2, and PHD3. The analysis involved both fresh frozen tumor samples as well as adjacent normal kidney tissues. Results: In ccRCC, HIF-1α and HIF-2α levels were upregulated in 65.5% and 71.4% of cases, respectively. PHD3 was downregulated only in 15.4% of the ccRCC cases, in contrast with oncocytoma cases, which exhibited low expression levels in the majority. The upregulation of PHD3 messenger RNA (mRNA) levels in ccRCC when compared with oncocytoma was statistically significant ( P<0.001). No other comparisons (HIF-1α, HIF-2α, PHD1, and PHD2) were significantly different. HIF-2α and PHD3 mRNA expression levels were negatively correlated with Fuhrman Grade ( P=0.029 and P=0.026, respectively) in ccRCC. Conclusion: To the best of our knowledge, this is the first time that the HIF/PHD pathway was compared between ccRCC and a common benign tumor, identifying the upregulation of PHD3 as the possible underlying factor guiding the difference in the behavior of ccRCC.

show abstract

“…The role of HIF-2a in ccRCC has recently emerged, and its expression may also affect the survival of patients. 9 Moreover, HIF-2a may be specifically targeted by small molecules, representing a new therapeutic target. 10 In prostate cancer, however, there are limited data with regard to the expression of the abovementioned proteins and their correlation with pathological and survival outcomes.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor 2a Expression Is Positively Correlated With Gleason Score in Prostate Cancer

Pavlakis

Kampantais

Gkagkalidis

et al. 2021

Technol Cancer Res Treat

Self Cite

View full text Add to dashboard Cite

Background: One of the main factors in response to hypoxia in the tumor microenvironment is the hypoxia-inducible factor (HIF) pathway. Although its role in other solid tumors, particularly renal cell carcinoma, has been sufficiently elucidated, it remains elusive in prostate cancer. The aim of the present study was to investigate the expression of main proteins involved in this pathway and determine the correlation of the results with clinicopathological outcomes of patients with prostate cancer. Methods: The immunohistochemical expression of HIF-1a, HIF-2a and their regulators, prolyl hydroxylase domain (PHD)1, PHD2 and PHD3 and factor inhibiting HIF (FIH), was assessed on a tissue microarray. This was constructed from radical prostatectomy specimens, involving both tumor and corresponding adjacent non-tumoral prostate tissues from 50 patients with localized or locally advanced prostate cancer. Results: In comparison with non-tumoral adjacent tissue, HIF-1a exhibited an equal or lower expression in 86% of the specimens (P = 0.017), while HIF-2a was overexpressed in 52% (P = 0.032) of the cases. HIF-1a protein expression was correlated with HIF-2a (P < 0.001), FIH (P = 0.004), PHD1 (P < 0.001), PHD2 (P < 0.001) and PHD3 (P = 0.035). HIF-2a expression was positively correlated with Gleason score (P = 0.017) and International Society of Urological Pathologists (ISUP) grade group (P = 0.022). Conclusions: The findings of the present study suggest a key role for HIF-2a in prostate cancer, as HIF-2a expression was found to be correlated with Gleason score and ISUP grade of the patients. However, further studies are required to validate these results and investigate the potential value of HIF-2a as a therapeutic target in prostate cancer.

show abstract

Expression of HIF-2a in clear-cell renal cell carcinoma independently predicts overall survival

Cited by 13 publications

References 24 publications

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

Decreased prolyl hydroxylase 3 mRNA expression in oncocytomas compared with clear cell renal cell carcinoma

Hypoxia-Inducible Factor 2a Expression Is Positively Correlated With Gleason Score in Prostate Cancer

Contact Info

Product

Resources

About