缺氧微环境下缺氧诱导因子-1α对前列腺癌细胞上皮间质转化的影响

doi:10.3969/j.issn.1006-7795.2014.03.003

首都医科大学学报 ›› 2014, Vol. 35 ›› Issue (3): 278-283.doi: 10.3969/j.issn.1006-7795.2014.03.003

• 泌尿外科基础临床研究 • 上一篇下一篇

缺氧微环境下缺氧诱导因子-1α对前列腺癌细胞上皮间质转化的影响

王永兴, 姜永光, 罗勇, 赵佳晖, 陈雅童, 韩毅力, 林云华

首都医科大学附属北京安贞医院泌尿外科北京市心肺血管疾病研究所, 北京 100029

收稿日期:2014-03-19 出版日期:2014-06-21 发布日期:2014-06-14
通讯作者: 姜永光，E-mail：yongguangjiang@126.com E-mail:yongguangjiang@126.com
基金资助:
国家自然科学基金（81341066）；北京市卫生系统高层次卫生技术人才基金（2013-2-003）；北京安贞医院院长科技发展基金（2013Z03）。

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

Wang Yongxing, Jiang Yongguang, Luo Yong, Zhao Jiahui, Chen Yatong, Han Yili, Lin Yunhua

Department of Urology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Diseases, Beijing 100029, China

Received:2014-03-19 Online:2014-06-21 Published:2014-06-14
Supported by:
This study was supported by the National Natural Science Foundation of China(81341066), Beijing Health System Special Foundation for Building High-level Health Personnel(2013-2-003), The Science and Technology Development Foundation of Anzhen Hospital(2013Z03).

摘要/Abstract

摘要：

目的探讨缺氧诱导因子-1α在缺氧的条件下对前列腺癌细胞发生上皮间质转化的影响。方法在缺氧的环境中培养前列腺癌细胞PC3，并应用分子生物学的方法检测其是否是发生上皮间质转化的关键转录因子。结果缺氧微环境可以诱导前列腺癌细胞PC3发生上皮间质转化，缺氧诱导因子-1α起关键的调节作用，并且可以增强前列腺癌细胞的侵袭能力。缺氧条件下抑制缺氧诱导因子-1α的表达可以阻止前列腺癌细胞发生上皮间质转化。结论缺氧微环境通过缺氧诱导因子-1α诱导前列腺癌细胞PC3发生上皮间质转化。

关键词: 缺氧微环境, 缺氧诱导因子-1α, 前列腺癌, 上皮间质转化

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

中图分类号:

R697

王永兴, 姜永光, 罗勇, 赵佳晖, 陈雅童, 韩毅力, 林云华. 缺氧微环境下缺氧诱导因子-1α对前列腺癌细胞上皮间质转化的影响[J]. 首都医科大学学报, 2014, 35(3): 278-283.

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.

参考文献

[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.

缺氧微环境下缺氧诱导因子-1α对前列腺癌细胞上皮间质转化的影响

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

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	刘群, 李丽娜, 刘健, 苗劲蔚. 卵巢癌SOX4介导TGF-β1诱导的上皮间质转化对侵袭转移能力的影响[J]. 首都医科大学学报, 2022, 43(3): 336-342.
[2]	蒋铭心, 苏瑶, 熊天宇, 叶小波, 靳松, 邢念增, 金木兰, 杨敏福, 牛亦农. 减瘤性根治性前列腺切除术对骨转移前列腺癌患者的临床疗效分析[J]. 首都医科大学学报, 2021, 42(6): 967-972.
[3]	王明帅, 熊天宇, 蒋铭心, 钱小松, 王思豪, 崔韵, 牛亦农. 改良前列腺尖部分离技术保留尿道周围结构对前列腺癌根治术后即刻尿控的影响[J]. 首都医科大学学报, 2021, 42(6): 973-977.
[4]	叶小波, 熊天宇, 崔韵, 王明帅, 杨辉, 安卓玲, 牛亦农. 醋酸阿比特龙联合强的松治疗去势抵抗型前列腺癌的疗效分析[J]. 首都医科大学学报, 2021, 42(6): 978-985.
[5]	樊笑琪, 刘志斌, 王明帅, 瓦斯里江·瓦哈甫, 宋黎明, 邢念增, 牛亦农. 腹腔镜单纯尿道前壁加强法与尿道前后壁加强法(Sandwich法)改善前列腺癌根治术后早期尿控的对比分析[J]. 首都医科大学学报, 2020, 41(4): 542-546.
[6]	白志杰, 王新胜, 马洪顺, 李波. mpMRI与超声融合导航技术在前列腺靶向穿刺的临床研究[J]. 首都医科大学学报, 2020, 41(4): 631-635.
[7]	李思泠, 朱钟慧, 李秋月, 许春杰, 赵静, 王炎, 田琳. Snail介导的肺上皮间质转化在肌成纤维细胞活化中的作用[J]. 首都医科大学学报, 2020, 41(1): 92-98.
[8]	谢英伟, 金仕鹏, 李爽, 王永辉, 王伟, 平浩, 刘跃新. TMPRSS2-ERG融合基因与转移性去势抵抗性前列腺癌化学药物治疗后生存率的关系[J]. 首都医科大学学报, 2020, 41(1): 103-107.
[9]	范晓娜, 姚健楠, 葛洋, 安广宇, 李鹰. DCLK1敲除对食管鳞癌细胞迁移和侵袭能力的影响[J]. 首都医科大学学报, 2019, 40(3): 417-423.
[10]	平浩, 马林祥, 王明帅, 龙军, 牛亦农, 刘跃新, 邢念增. 单羧酸转运蛋白4(MCT4)在前列腺癌中的表达及调控研究[J]. 首都医科大学学报, 2019, 40(1): 59-64.
[11]	王蔚, 苏嘉明, 袁东波, 张伟, 陈卫红, 孙兆林, 朱建国. 微管相关蛋白1A在前列腺癌中的表达与其临床特征的关系[J]. 首都医科大学学报, 2019, 40(1): 65-71.
[12]	谢英伟, 金世鹏, 闫伟, 王伟, 平浩, 刘跃新. TMPRSS2-ERG融合基因在淋巴结转移前列腺癌中的阳性率及与生存的关系[J]. 首都医科大学学报, 2019, 40(1): 72-77.
[13]	左灵坤, 阳荣辉, 马慧, 周萍, 孔璐. 生物信息学方法分析前列腺癌组织及细胞系中LMNA基因第七外显子点突变[J]. 首都医科大学学报, 2017, 38(6): 884-890.
[14]	张继伟, 阎乙夫, 夏溟. 低危前列腺癌¹²⁵I粒子植入治疗尿路合并症的临床分析[J]. 首都医科大学学报, 2017, 38(2): 325-328.
[15]	瓦斯里江·瓦哈甫, 牛亦农, 邢念增. 前列腺癌化疗的发展及未来[J]. 首都医科大学学报, 2016, 37(3): 299-306.