Neuroendocrine (NE) differentiation in prostate cancer has been correlated with a poor prognosis and hormone refractory disease. In a previous report, we demonstrated the presence of immunoreactive cytoplasmic hypoxia inducible factor 1alfa (HIF1alfa), in both benign and malignant NE prostate cells. HIF1alfa and HIF1beta are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stablization of HIF1alfa in androgen-independent NE differentiated prostate cancer is due to the presence of certain HIF1alfa isoforms.

We studied the HIF1alfa isoforms present in 8 cases of benign prostate hyperplasia and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization.

We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1alfa1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1alfa immunoreactive prostate tumors and 100% of cases of benign prostate hyperplasia. Immunohistochemistry and in situ hybridization results showed that this isoform corresponds to the cytoplasmic HIF1alfa present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1beta.

Our results indicate that the cytoplasmic stablization of HIF1alfa in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1alfa isoform, HIF1alfa1.2. Co-localization of this isoform with HIF1beta indicated that the HIF1alfa1.2 isoform might sequester HIF1beta in the cytoplasm.

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