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

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 nephrec-tomy. 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.

Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo

“…We observed varying levels of HIF1α, HIF2α, PHD3, and VHL expression among 9 RCC cell lines, which supports previous studies showing that RCC depends on hypoxia pathways [ 1 , 4 , 6 , 16 ]. The knockdown of PHD3 in the UMRC3 ccRCC cell line led to increased tumor growth in mouse models which was inhibited by sunitinib treatment.…”

Hypoxia-Driven Immune Escape in the Tumor Microenvironment

“…Based on the studies highlighted in this section, hypoxia and HIF transcription factors heavily contribute to different forms of resistance to immunotherapy (Figure 4). This is in line with studies that correlate high HIF expression with poor prognostic outcomes in several cancers [122][123][124]. Altogether, selective targeting of HIF in tumors is an attractive therapeutic approach that may bolster immunotherapeutic agents and prevent hypoxia-mediated resistance to immunotherapy.…”

<p>Mutational Characterization and Potential Prognostic Biomarkers of Chinese Patients with Esophageal Squamous Cell Carcinoma</p>

“…The mutation of FOS is reportedly associated with poor prognosis in colorectal cancer, 55 and high expression of DOT1L and VEGFA indicates poor prognosis in many cancers, such as lung cancer, gastric cancer, and clear cell renal cell carcinoma. [56][57][58][59] These reports imply that mutation of these genes is potentially associated with the Figure 6 The correlation between metastatic lymph node status and the prognosis of ESCC patients. (A) The differential analysis of disease-free survival of patients with and without metastatic lymph nodes.…”