单羧酸转运蛋白4(MCT4)在前列腺癌中的表达及调控研究

doi:10.3969/j.issn.1006-7795.2019.01.011

首都医科大学学报 ›› 2019, Vol. 40 ›› Issue (1): 59-64.doi: 10.3969/j.issn.1006-7795.2019.01.011

• 泌尿系统肿瘤：基础研究与临床实践 • 上一篇下一篇

单羧酸转运蛋白4(MCT4)在前列腺癌中的表达及调控研究

平浩¹, 马林祥², 王明帅², 龙军³, 牛亦农², 刘跃新¹, 邢念增⁴

1. 首都医科大学附属北京同仁医院泌尿外科, 北京 100730;
2. 首都医科大学附属北京朝阳医院泌尿外科, 北京 100020;
3. 首都医科大学基础医学院免疫学系, 北京 100069;
4. 国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院, 北京 100021

收稿日期:2018-10-24 出版日期:2019-01-21 发布日期:2019-01-23
通讯作者: 平浩 E-mail:pinghaocy@163.com
基金资助:
国家自然科学基金（面上项目）（81772698），首都医科大学基础临床科研合作基金（16JL60）。

Expression and regulation of monocarboxylate transporters 4(MCT4) in prostate cancer

Ping Hao¹, Ma Linxiang², Wang Mingshuai², Long Jun³, Niu Yinong², Liu Yuexin¹, Xing Nianzeng⁴

1. Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China;
2. Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China;
3. Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China;
4. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Received:2018-10-24 Online:2019-01-21 Published:2019-01-23
Supported by:
This study was supported by National Natural Science Foundation of China(81772698), Basic-Clinical Cooperation Program from Capital Medical University(16JL60).

摘要/Abstract

摘要： 目的探讨单羧酸转运蛋白4（monocarboxylate transporters 4，MCT4）在前列腺癌组织及细胞系中的表达情况，明确其在前列腺癌细胞中的调控作用。方法应用免疫组织化学方法检测MCT4蛋白在前列腺癌（prostate cancer，PCa）、良性前列腺增生（benign prostatic hyperplasia，BPH）及癌旁组织（para-carcinoma tissues，PCT）中的表达，分析其与前列腺癌Gleason评分及淋巴结转移的关系。免疫印迹（Western blotting）法检测不同前列腺癌细胞系中MCT4蛋白表达差异，分析抑制MCT4蛋白表达对N-cadherin、E-cadherin及pERK1/2的调控作用。结果免疫组化检测显示，MCT4蛋白在前列腺癌、前列腺增生及癌旁组织中均有表达；但PCa中MCT4表达水平明显高于BPH及PCT（P=0.003）。另外，MCT4蛋白表达与前列腺癌是否有淋巴结转移密切相关，转移组显著高于非转移组（P=0.022）。Western blotting检测结果显示，在前列腺正常上皮细胞及激素依赖性前列腺癌细胞LNCap中MCT4表达较弱，而在恶性程度较高的去势抵抗性前列腺癌细胞PC3及DU145中表达明显增强。抑制PC3细胞中MCT4表达可以使N-cadherin及pERK1/2的蛋白表达下降，而使E-cadherin蛋白表达水平升高。结论单羧酸转运蛋白4可能参与上皮间质转化（epithelial-mesenchymal transition，EMT）进程及ERK1/2通路的调控，促进前列腺癌的进展和转移，对前列腺癌的临床诊断和治疗有重要意义。

关键词: 前列腺癌, 单羧酸转运蛋白4, 淋巴结转移, 调控作用

Abstract: Objective To investigate the expression and clinical significance of monocarboxylate transporters 4(MCT4) in prostate cancer(PCa), and explore the regulation mechanism of MCT4 in PCa. Methods The expression of MCT4 was detected by immunohistochemistry in PCa, benign prostatic hyperplasia(BPH) and para-carcinoma tissues(PCT). The relation between the expression and clinicopathological changes was analyzed statistically. The expression of MCT4 was examined with Western blotting in prostate cancer cells. The effects on N-cadherin, E-cadherin and pERK1/2 by inhibition of MCT4 was also analyzed. Results The expression of MCT4 in PCa was significantly higher than those in BPH and PCT (P=0.003). Furthermore, the increased expression of MCT4 protein was significantly associated with the presence of lymph node metastasis of PCa(P=0.022). The Western blotting indicated that, the expression of MCT4 protein was higher in PC3 and DU145 than in RWPE-1 and LNCap cell lines. With inhibition of MCT4, the level of N-cadherin and pERK1/2 was decreased, while that of E-cadherin was increased. Conclusion The expression of MCT4 may be involved in the regulation of epithelial-mesenchymal transition (EMT) and ERK1/2, and it is closely related to the metastasis of PCa. The expression of MCT4 has significant clinical implications for diagnosis and treatment of PCa.

Key words: prostate cancer, monocarboxylate transporters 4, lymph node metastasis, regulation

中图分类号:

R737.25

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.

Ping Hao, Ma Linxiang, Wang Mingshuai, Long Jun, Niu Yinong, Liu Yuexin, Xing Nianzeng. Expression and regulation of monocarboxylate transporters 4(MCT4) in prostate cancer[J]. Journal of Capital Medical University, 2019, 40(1): 59-64.

参考文献

[1] Siegel R L, Miller K D, Jemal A. Cancer statistics, 2018[J]. CA Cancer J Clin,2018, 68(1):7-30.
[2] Choi J W, Kim Y, Lee J H, et al. Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder[J]. Urology, 2014, 84(1):245.e9-15.
[3] Kim H K, Lee I, Bang H, et al. MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis[J]. Mol Cancer Ther, 2018, 17(4):838-848.
[4] Pértega-Gomes N, Vizcaíno J R, Attig J, et al. A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer[J]. BMC Cancer, 2014, 14:352.
[5] Li Z, Wu Q, Sun S, et al. Monocarboxylate transporters in breast cancer and adipose tissue are novel biomarkers and potential therapeutic targets[J]. Biochem Biophys Res Commun, 2018, 501(4):962-967.
[6] Sanità P, Capulli M, Teti A, et al. Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression[J]. BMC Cancer, 2014,14:154.
[7] 薛炜,邱建新,桑楠,等.Oct4蛋白对前列腺癌雄激素剥夺治疗后进展速度的预测价值分析[J].解放军医药杂志,2018,30(7):22-25,30.
[8] Ceder Y, Bjartell A, Culig Z, et al. The molecular evolution of castration-resistant prostate cancer[J]. Eur Urol Focus, 2016, 2(5):506-513.
[9] Sormendi S, Wielockx B. Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment[J]. Front Immunol, 2018, 9:40.
[10] Baltazar F, Pinheiro C, Morais-Santos F, et al. Monocarboxylate transporters as targets and mediators in cancer therapy response[J]. Histol Histopathol,2014, 29(12):1511-1524.
[11] Zhu J, Wu Y N, Zhang W, et al. Monocarboxylate transporter 4 facilitates cell proliferation and migration and is associated with poor prognosis in oral squamous cell carcinoma patients[J]. PLoS One, 2014, 9(1):e87904.
[12] Bovenzi C D, Hamilton J, Tassone P, et al. Prognostic indications of elevated MCT4and CD147 across cancer types:a Meta-analysis[J]. Biomed Res Int, 2015, 2015:242437.
[13] Choi S Y, Xue H, Wu R, et al. The MCT4 Gene:a novel, potential target for therapy of advanced prostate cancer[J]. Clin Cancer Res, 2016,22(11):2721-2733.
[14] Kelsey R. Prostate cancer:MCT4 is a novel target for prostate cancer[J]. Nat Rev Urol,2016, 13(3):123.
[15] Gao H J, Zhao M C, Zhang Y J, et al. Monocarboxylate tansporter 4 predicts poor prognosis in hepatocellular carcinoma and is associate with cell proliferation andmigration[J]. J Cancer Res Clin Oncol, 2015,141(7):1151-1162.
[16] Todenhöfer T, Seiler R, Stewart C, et al. Selective inhibition of the lactate transporter MCT4 reduces growth of invasive bladder cancer[J]. Mol Cancer Ther,2018, 17(12):2746-2755.
[17] Gerlinger M, Santos C R, Spencer-Dene B, et al. Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target[J]. J Pathol, 2012, 227(2):146-156.
[18] Wilde L, Roche M, Domingo-Vidal M, et al. Metabolic coupling and the reverse warburg effect in cancer:Implications for novel biomarker and anticancer agent development[J]. Semin Oncol, 2017, 44(3):198-203.
[19] Choi S Y C, Ettinger S L, Lin D, et al. Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer[J]. Cancer Med, 2018,7(7):3385-3392.

单羧酸转运蛋白4(MCT4)在前列腺癌中的表达及调控研究

Expression and regulation of monocarboxylate transporters 4(MCT4) in prostate cancer

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]	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.
[2]	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.
[3]	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.
[4]	王亚军, 康骅, 赵菁, 海涛, 张小丽, 蔡伟. 甲状腺微小乳头状癌中央区淋巴结转移影响因素的聚类分析研究[J]. 首都医科大学学报, 2021, 42(6): 1053-1059.
[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]	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.
[8]	姜波, 罗渝昆, 张艳, 田晓琦, 张颖, 谢芳, 宋青, 唐杰. 甲状腺乳头状癌的常规超声及超声造影特征与淋巴结转移的相关性[J]. 首都医科大学学报, 2019, 40(6): 818-823.
[9]	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.
[10]	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.
[11]	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.
[12]	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.
[13]	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.
[14]	孙剑, 靳松, 赵宏颖, 刘洋, 金木兰, 邢念增, 牛亦农. 5-α还原酶的表达与前列腺癌生物学行为相关性研究[J]. 首都医科大学学报, 2016, 37(3): 307-312.
[15]	刘志斌, 靳松, 张军晖, 王建文, 田溪泉, 田龙, 牛亦农, 邢念增. 腹腔镜Sandwich法尿道及周围组织重建改善高风险组前列腺癌根治术后早期尿控的研究[J]. 首都医科大学学报, 2016, 37(3): 313-317.