HIF1alpha isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation.
BACKGROUND
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 1alpha (HIF1alpha), in both benign and malignant NE prostate cells. HIF1alpha and HIF1beta are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stabilization of HIF1alpha in androgen independent NE differentiated prostate cancer is due to the presence of certain HIF1alpha isoforms.


METHODS
We studied the HIF1alpha isoforms present in 8 cases of benign prostate hyperplasia (BPH) and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization.


RESULTS
We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1alpha1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1alpha 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 HIF1alpha present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1beta.


CONCLUSIONS
Our results indicate that the cytoplasmic stabilization of HIF1alpha in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1alpha isoform, HIF1alpha1.2. Co-localization of this isoform with HIF1beta indicates that the HIF1alpha1.2 isoform might sequester HIF1beta in the cytoplasm.
Monsef
Nastaran
N
Department of Laboratory Medicine, Division of Pathology, Lund University Hospital, Sweden. Nastaran.Monsef@gmail.com
Soller
Maria
M
Panagopoulos
Ioannis
I
Abrahamsson
Per Anders
PA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009490:Neurosecretory Systems / Q000473:pathology*; D011379:Prognosis; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D012333:RNA, Messenger