Hypoxia inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells

doi:10.3969/j.issn.1006-7795.2014.03.003

Abstract

Abstract:

Objective To explore the influence of hypoxia-inducible factor-1α(HIF-1α) on prostate cancer epithelial to mesenchymal transition(EMT) under hypoxic conditions. Methods In this study we carried out several methods in molecular biology to test whether PC3, a human prostate cancer cell line, underwent typical epithelial to mesenchymal transition under hypoxia and the key regulator of this process. Results We demonstrated that hypoxia induced diverse molecular, phenotypic, and functional changes in prostate cancer cells that are consistent with EMT. We also showed that HIF-1α, which is thought to be stabilized under hypoxic environment, is involved in EMT and cancer cell invasive potency. Hypoxia-induced EMT in prostate cancer cells is blocked by HIF-1α gene silencing. Conclusion EMT may be induced in hypoxic prostate cancer cells, by a mechanism that involves activation of HIF-1α-dependent cell signaling.

Key words: hypoxic environment, hypoxia-inducible factor-1α, prostate cancer, epithelial to mesenchymal transition

CLC Number:

R697

Wang Yongxing, Jiang Yongguang, Luo Yong, Zhao Jiahui, Chen Yatong, Han Yili, Lin Yunhua. Hypoxia inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells[J]. Journal of Capital Medical University, 2014, 35(3): 278-283.

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URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2014.03.003

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2014/V35/I3/278

References

[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013[J]. CA Cancer J Clin, 2013, 63(1):11-30.
[2] Vaupel P, Kelleher D K, Hockel M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy[J]. Semin Oncol, 2001, 28(2 Suppl 8):29-35.
[3] Evans S M, Koch C J. Prognostic significance of tumor oxygenation in humans[J]. Cancer Lett, 2003, 195(1):1-16.
[4] Parker C, Milosevic M, Toi A, et al. Polarographic electrode study of tumor oxygenation in clinically localized prostate cancer[J]. Int J Radiat Oncol Biol Phys, 2004, 58(3):750-757.
[5] Cvetkovic D, Movsas B, Dicker A P, et al. Increased hypoxia correlates with increased expression of the angiogenesis marker vascular endothelial growth factor in human prostate cancer[J]. Urology, 2001, 57(4):821-825.
[6] Movsas B, Chapman J D, Greenberg R E, et al. Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: An Eppendorf po(2) study[J]. Cancer, 2000, 89(9):2018-2024.
[7] Carnell D M, Smith R E, Daley F M, et al. An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: implications for radioresistance[J]. Int J Radiat Oncol Biol Phys, 2006, 65(1):91-99.
[8] Vergis R, Corbishley C M, Norman A R, et al. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: A retrospective analysis of two randomised radiotherapy trials and one surgical cohort study[J]. Lancet Oncol, 2008, 9(4):342-351.
[9] Berx G, Raspe E, Christofori G, et al. Pre-EMTting metastasis? Recapitulation of morphogenetic processes in cancer[J]. Clin Exp Metastasis, 2007, 24(8):587-597.
[10] Morel A P, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition[J]. PLoS One, 2008, 3(8):e2888.
[11] Hollier B G, Evans K, Mani S A. The epithelial-to-mesenchymal transition and cancer stem cells: A coalition against cancer therapies[J]. J Mammary Gland Biol Neoplasia, 2009, 14(1):29-43.
[12] Derksen P W, Liu X, Saridin F, et al. Somatic inactivation of e-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis[J]. Cancer Cell, 2006, 10(5):437-449.
[13] Cano A, Perez-Moreno M A, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing e-cadherin expression[J]. Nat Cell Biol, 2000, 2(2):76-83.
[14] Bolos V, Peinado H, Perez-Moreno M A, et al. The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors[J]. J Cell Sci, 2003, 116(Pt 3):499-511.
[15] Yang J, Mani S A, Donaher J L, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis[J]. Cell, 2004, 117(7):927-939.
[16] Nieto M A. The snail superfamily of zinc-finger transcription factors[J]. Nat Rev Mol Cell Biol, 2002, 3(3):155-166.
[17] Savagner P, Yamada K M, Thiery J P. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition[J]. J Cell Biol, 1997, 137(6):1403-1419.
[18] Cannito S, Novo E, Compagnone A, et al. Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells[J]. Carcinogenesis, 2008, 29(12):2267-2278.
[19] Vaupel P, Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome[J]. Cancer Metastasis Rev, 2007, 26(2):225-239.
[20] Brown J M. The hypoxic cell: A target for selective cancer therapy eighteenth Bruce F. Cain memorial Award lecture[J]. Cancer Res, 1999, 59(23):5863-5870.
[21] Tatum J L, Kelloff G J, Gillies R J, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy[J]. Int J Radiat Biol, 2006, 82(10):699-757.
[22] Hockel M, Schlenger K, Hockel S, et al. Hypoxic cervical cancers with low apoptotic index are highly aggressive[J]. Cancer Res, 1999, 59(18):4525-4528.
[23] Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects[J]. J Natl Cancer Inst, 2001, 93(4):266-276.
[24] Moen I, Oyan A M, Kalland K H, et al. Hyperoxic treatment induces mesenchymal-to-epithelial transition in a rat adenocarcinoma model[J]. PLoS One, 2009, 4(7):e6381.
[25] 韩毅力, 程永毅, 徐永刚.低氧条件下HIF-1α对HGF表达影响的观察[J].中华肿瘤防治杂志, 2012, 18(18):1377-1379.
[26] Jiang Y G, Luo Y, He D L, et al. Role of wnt/beta-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha[J]. Int J Urol, 2007, 14(11):1034-1039.
[27] Yang M H, Wu M Z, Chiou S H, et al. Direct regulation of twist by hif-1alpha promotes metastasis[J]. Nat Cell Biol, 2008, 10(3):295-305.
[28] Imai T, Horiuchi A, Wang C, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells[J]. Am J Pathol, 2003, 163(4):1437-1447.
[29] Krishnamachary B, Berg-Dixon S, Kelly B, et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1[J]. Cancer Res, 2003, 63(5):1138-1143.
[30] 倪嘉延, 吴裕丹, 黄康华, 等.HIF-1α基因干扰对大鼠CBRH-7919肝癌细胞HIF-1α与VEGF表达影响的研究[J].中华肿瘤防治杂志, 2012, 18(22):1704-1708.
[31] Giaccia A, Siim B G, Johnson R S. HIF-1 as a target for drug development[J]. Nat Rev Drug Discov, 2003, 2(10):803-811.
[32] Belozerov V E, Van Meir E G. Hypoxia inducible factor-1: a novel target for cancer therapy[J]. Anticancer Drugs, 2005, 16(9):901-909.
[33] Melillo G. Inhibiting hypoxia-inducible factor 1 for cancer therapy[J]. Mol Cancer Res, 2006, 4(9):601-605.
[34] Brown L M, Cowen R L, Debray C, et al. Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1[J]. Mol Pharmacol, 2006, 69(2):411-418.
[35] Hofer T, Desbaillets I, Hopfl G, et al. Characterization of HIF-1 alpha overexpressing HeLa cells and implications for gene therapy[J]. Comp Biochem Physiol C Toxicol Pharmacol, 2002, 133(4):475-481.
[36] Du R, Huang C, Bi Q, et al. URG11 mediates hypoxia-induced epithelial-to-mesenchymal transition by modulation of E-cadherin and beta-catenin[J]. Biochem Biophys Res Commun, 2010, 391(1):135-141.
[37] Zhou B P, Deng J, Xia W, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition[J]. Nat Cell Biol, 2004, 6(10):931-940.
[38] Singh A, Settleman J. Emt, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer[J]. Oncogene, 2010, 29(34):4741-4751.