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

Abstract

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.

TXNIP knockout improves cardiac function after myocardial infarction by promoting angiogenesis and reducing cardiomyocyte apoptosis

“…As we all know, the transcription and stability of HIF-1α are regulated by enzymes. At the transcription level, HIF inhibitor (FIH) inhibits the transcription activity of HIF-1α, thereby down-regulating the expression level of HIF-1α (17). At the protein level, HIF-1α is an unstable protein with a short half-life, even less than 5 minutes.…”

“…PHD can make the proline residues in the HIF-1α molecule hydroxylated, and finally recognized and degraded by the proteasome, thus affecting the protein stability of HIF-1α (16). FIH inhibits the transcriptional activity of HIF-1α by blocking the binding of the transcription activation domain of HIF-1α to CREB binding protein (CBP)/p300 (17). However, the effect of TXNIP on the expression of PHD and FIH is still unclear.…”

Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma

“…HIF-3α is an inhibitor of hypoxic transcriptional response. Therefore, HIF induces the production of a number of gene products and controls energetic metabolism and pH in cells, which can affect TME [ 91 , 92 ]. TME features are associated with resistance to ICI therapy in some studies [ [93] , [94] , [95] ].…”

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

“…This is driven not only by hypoxia but also by mechanisms that are independent of the O 2 content of the tumour and more related to dysregulation of cell metabolism and duplication [143]. The higher the HIF expression, the more aggressive is the tumour and the worse the patient outcome in several solid cancers [144,145] or hematologic neoplasms. Hypoxia-inducible factor activation can contribute to tumour growth and progression by activating several genes controlling angiogenesis, anaerobic metabolism, cell cycle, epithelial-mesenchymal transition, cell motility, and immune evasion [140].…”