Overexpression of the Oxygen Sensors PHD-1, PHD-2, PHD-3, and FIH Is Associated with Tumor Aggressiveness in Pancreatic Endocrine Tumors

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Abstract
Purpose: Tumor hypoxia is associated with poor prognosis and resistance to treatment. Our aim was to assess the expression of proteins that act as cellular oxygen sensors, directly regulating the hypoxia inducible factor (HIF) pathway, i.e., prolyl hydroxylase domain proteins (PHD)-1, PHD-2, PHD-3, and FIH in pancreatic endocrine tumors (PET). Experimental Design: Immunohistochemical expression of these markers was examined in 109 PET included in tissue microarrays and representing various stages of tumorigenesis. The results were correlated with histoprognostic factors including Ki-67 index, presence of a fibrotic focus, and microvascular density (MVD). Results: The cytoplasmic and nuclear expressions of the three PHD isoforms were associated, and their expression was significantly higher in aggressive PETS, malignant, with lymph node metastases or with lower MVD. High nuclear expression of the three isoforms highly correlated with HIF-1α nuclear expression (P = 0.02, 0.003, and 0.006, respectively). Moreover, high nuclear PHD-1 or PHD-3 expression was associated with a poorer survival (P = 0.01). Cytoplasmic FIH was significantly higher in malignant PETs (P = 0.05) and in PETs with lymph node metastases (P = 0.02), and its expression correlated positively with those of cytoplasmic PHD isoforms (P < 0001). FIH stromal expression was found in 23% of PETs and correlated with higher FIH nuclear expression (P = 0.0004) and poorer disease-free survival (P = 0.0018). Conclusion: HIF regulatory proteins are highly expressed in PET and their expression is correlated with tumor metastases, tumor recurrence, and prognosis. These molecules that play an important role in the control of hypoxia-induced genes may have a function in the regulation of cellular proliferation and differentiation during endocrine tumorigenesis.