Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

Wierzbicki,Piotr  M.; Klacz,Jakub; Kotulak‑Chrzaszcz,Anna; Wronska,Agata; Stanislawowski,Marcin; Rybarczyk,Agnieszka; Ludziejewska,Aleksandra; Kmiec,Zbigniew; Matuszewski,Marcin

doi:10.3892/ijo.2019.4830

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

Authors:
- Piotr M. Wierzbicki
- Jakub Klacz
- Anna Kotulak‑Chrzaszcz
- Agata Wronska
- Marcin Stanislawowski
- Agnieszka Rybarczyk
- Aleksandra Ludziejewska
- Zbigniew Kmiec
- Marcin Matuszewski
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Affiliations: Department of Histology, Faculty of Medicine, Medical University of Gdansk, 80211 Gdansk, Poland, Department of Urology, Faculty of Medicine, Medical University of Gdansk, 80402 Gdansk, Poland, Department of Laboratory Diagnostics, Medical University of Poznan, 61701 Poznan, Poland
Published online on: June 25, 2019 https://doi.org/10.3892/ijo.2019.4830
Pages: 371-390
Copyright: © Wierzbicki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer, characterized by the highest mortality rate among other RCC subtypes due to the occurrence of metastasis and drug resistance following surgery. The Von Hippel‑Lindau tumor suppressor (VHL)‑hypoxia‑inducible factor 1 subunit α (HIF1A)/hypoxia‑inducible factor 2α (HIF2A)‑vascular endothelial growth factor A (VEGFA) protein axis is involved in the development and progression of ccRCC, whereas sunitinib, a tyrosine kinase inhibitor, blocks the binding of VEGFA to its receptor. The aim of the present study was to examine the possible association of the gene expression of VHL, HIF1A, HIF2A, VEGFA and tumor protein P53 (P53) in cancer tissue with the outcome of ccRCC patients who were treated with sunitinib as first‑line therapy following nephrectomy. A total of 36 ccRCC patients were enrolled, 11 of whom were administered sunitinib post‑operatively. Tumor and control samples were collected, and mRNA and protein levels were assessed by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. High mRNA and protein expression levels of HIF2A and VEGFA were found to be associated with shorter overall survival (OS) and progression‑free survival (PFS) rates, as well as with unfavorable risk factors of cancer recurrence and mortality. Resistance to sunitinib was also observed; the OS and PFS rates were shorter (median OS and PFS: 12 and 6 months, respectively, vs. undetermined). Sunitinib resistance was associated with high HIF2A and VEGFA protein levels (b=0.57 and b=0.69 for OS and PFS, respectively; P<0.001). Taken together, the findings of this study suggest that the protein levels of HIF2A and VEGFA in tumor tissue may serve as independent prognostic factors in ccRCC. ccRCC patients with increased intratumoral HIF2A and VEGFA protein levels, and unaltered VHL protein levels, are not likely to benefit from sunitinib treatment following nephrectomy; however, this hypothesis requires verification by large‑scale replication studies.

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