HIF1alpha Isoforms in Benign and Malignant Prostate Tissue and Their Correlation to Neuroendocrine Differentiation

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2010 Jul 29

PMID 20663134

Citations 5

Authors

Nastaran Monsef

Maria Soller

Ioannis Panagopoulos

Per Anders Abrahamsson

Affiliations

Soon will be listed here.

Abstract

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.

Conclusion: 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.

Citing Articles

Human Red Blood Cells Modulate Cytokine Expression in Monocytes/Macrophages Under Anoxic Conditions.

Antonelli A, Scarpa E, Magnani M Front Physiol. 2021; 12:632682.

PMID: 33679443 PMC: 7930825. DOI: 10.3389/fphys.2021.632682.

Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma.

Krivtsova O, Makarova A, Lazarevich N World J Hepatol. 2018; 10(10):645-661.

PMID: 30386458 PMC: 6206146. DOI: 10.4254/wjh.v10.i10.645.

Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation.

Jou Y, Tsai Y, Lin C, Tung C, Shen C, Tsai H Oncotarget. 2016; 7(40):65403-65417.

PMID: 27557492 PMC: 5323164. DOI: 10.18632/oncotarget.11395.

Normoxic regulation of HIF-1α in prostate cancer.

Ranasinghe W, Baldwin G, Shulkes A, Bolton D, Patel O Nat Rev Urol. 2014; 11(7):419.

PMID: 24980197 DOI: 10.1038/nrurol.2013.110-c2.

The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.

Ranasinghe W, Xiao L, Kovac S, Chang M, Michiels C, Bolton D PLoS One. 2013; 8(1):e54251.

PMID: 23342109 PMC: 3546972. DOI: 10.1371/journal.pone.0054251.

References

Luo Y, He D, Ning L, Shen S, Li L, Li X . Hypoxia-inducible factor-1alpha induces the epithelial-mesenchymal transition of human prostatecancer cells. Chin Med J (Engl). 2006; 119(9):713-8. View

Boddy J, Fox S, Han C, Campo L, Turley H, Kanga S . The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer. Clin Cancer Res. 2005; 11(21):7658-63. DOI: 10.1158/1078-0432.CCR-05-0460. View

Chun Y, Choi E, Kim T, Kim M, Park J . A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1alpha gene. Biochem J. 2002; 362(Pt 1):71-9. PMC: 1222361. DOI: 10.1042/0264-6021:3620071. View

Rudolfsson S, Bergh A . Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1alpha. J Endocrinol. 2008; 196(1):11-9. DOI: 10.1677/JOE-07-0272. View

Depping R, Hagele S, Wagner K, Wiesner R, Camenisch G, Wenger R . A dominant-negative isoform of hypoxia-inducible factor-1 alpha specifically expressed in human testis. Biol Reprod. 2004; 71(1):331-9. DOI: 10.1095/biolreprod.104.027797. View

Carraway R, Hassan S . Neurotensin receptor binding and neurotensin-induced growth signaling in prostate cancer PC3 cells are sensitive to metabolic stress. Regul Pept. 2007; 141(1-3):140-53. DOI: 10.1016/j.regpep.2006.12.027. View

Horii K, Suzuki Y, Kondo Y, Akimoto M, Nishimura T, Yamabe Y . Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells. Mol Cancer Res. 2007; 5(4):383-91. DOI: 10.1158/1541-7786.MCR-06-0226. View

Rinaldo F, Li J, Wang E, Muders M, Datta K . RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation. Oncogene. 2006; 26(12):1731-8. DOI: 10.1038/sj.onc.1209971. View

Hao P, Chen X, Geng H, Gu L, Chen J, Lu G . Expression and implication of hypoxia inducible factor-1alpha in prostate neoplasm. J Huazhong Univ Sci Technolog Med Sci. 2005; 24(6):593-5. DOI: 10.1007/BF02911365. View

10.

Bonkhoff H, Fixemer T . [Neuroendocrine differentiation in prostate cancer: an unrecognized and therapy resistant phenotype]. Pathologe. 2005; 26(6):453-60. DOI: 10.1007/s00292-005-0791-0. View

11.

Monsef N, Helczynski L, Lundwall A, Pahlman S . Localization of immunoreactive HIF-1alpha and HIF-2alpha in neuroendocrine cells of both benign and malignant prostate glands. Prostate. 2007; 67(11):1219-29. DOI: 10.1002/pros.20594. View

12.

Dizeyi N, Bjartell A, Nilsson E, Hansson J, Gadaleanu V, Cross N . Expression of serotonin receptors and role of serotonin in human prostate cancer tissue and cell lines. Prostate. 2004; 59(3):328-36. DOI: 10.1002/pros.10374. View

13.

Semenza G . Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life. 2008; 60(9):591-7. DOI: 10.1002/iub.93. View

14.

Kimbro K, Simons J . Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer. 2006; 13(3):739-49. DOI: 10.1677/erc.1.00728. View

15.

Vashchenko N, Abrahamsson P . Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol. 2005; 47(2):147-55. DOI: 10.1016/j.eururo.2004.09.007. View

16.

Siddiqui E, Shabbir M, Mikhailidis D, Thompson C, Mumtaz F . The role of serotonin (5-hydroxytryptamine1A and 1B) receptors in prostate cancer cell proliferation. J Urol. 2006; 176(4 Pt 1):1648-53. DOI: 10.1016/j.juro.2006.06.087. View

17.

Park S, Kim Y, Gao A, Mohler J, Onate S, Hidalgo A . Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Res. 2006; 66(10):5121-9. DOI: 10.1158/0008-5472.CAN-05-1341. View

18.

Niu G, Wright K, Huang M, Song L, Haura E, Turkson J . Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002; 21(13):2000-8. DOI: 10.1038/sj.onc.1205260. View

19.

Chun Y, Lee K, Choi E, Bae S, Yeo E, Huang L . Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1alpha isoform: implications for tumor promotion. Cancer Res. 2003; 63(24):8700-7. View

20.

Gothie E, Richard D, Berra E, Pages G, Pouyssegur J . Identification of alternative spliced variants of human hypoxia-inducible factor-1alpha. J Biol Chem. 2000; 275(10):6922-7. DOI: 10.1074/jbc.275.10.6922. View