生物钟基因Period2调节肝癌细胞warburg效应及转移侵袭中的作用机制

doi:10.12092/j.issn.1009-2501.2019.10.008

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (10): 1134-1141.doi: 10.12092/j.issn.1009-2501.2019.10.008

生物钟基因Period2调节肝癌细胞warburg效应及转移侵袭中的作用机制

赵巧素¹，叶桦¹，孙勤学²

¹宁波市医疗中心李惠利医院消化内科, ²放射科，宁波 315000，浙江

收稿日期:2019-04-19 修回日期:2019-06-03 出版日期:2019-10-26 发布日期:2019-10-28
通讯作者: 孙勤学，男，博士，副主任医师，硕导，研究方向：肝癌肝脏纤维化肝硬化。 E-mail：sqxue@163.com
作者简介:赵巧素,女，硕士研究生，主治医师，研究方向：肝癌肝硬化。 E-mail： zhaoqiaosu_2@163.com
基金资助:
浙江省医药卫生科技计划项目（2019KY185）

Effects of circadian clock gene Period2 on Warburg effect and metastasis in hepatocellular carcinoma cells

ZHAO Qiaosu¹，YE Hua¹，SUN Qinxue²

¹ Department of Gastroenterology，²Department of Radiology，Ningbo Medical Center Li Huili Hospital，Ningbo 315000，Zhejiang，China

Received:2019-04-19 Revised:2019-06-03 Online:2019-10-26 Published:2019-10-28

摘要/Abstract

摘要：

目的:研究钟基因Period2在肝癌细胞warburg效应及转移侵袭中的作用。方法:采用实时荧光定量PCR（RT-QPCR）检测组织以及肝癌细胞的Period2表达水平。上调肝癌细胞MHCC97L中Period2的水平，沉默HepG2中Period2的表达。检测葡萄糖摄取水平、乳酸水平、细胞氧耗水平、细胞活力、迁移能力、侵袭能力。Western-Blot检测细胞中代谢关键酶的表达。结果:肿瘤组织中Period2基因水平显著高于癌旁组织（P<0.05）。4株肿瘤细胞中MHCC97L中Period2表达水平较低，而HepG2水平较高。Period2沉默后，HepG2细胞葡萄糖相对摄取水平相比control下调、乳酸相对产生水平相比control下调，细胞耗氧量相比control增高，细胞活力、迁移及侵袭能力下降。糖代谢关键酶表达水平下调。而Period2过表达后，MHCC97L细胞葡萄糖摄取水平相比control增高、乳酸产生水平相比control上调，细胞耗氧量相比control降低，细胞活力、迁移及侵袭能力上调。糖代谢关键酶表达水平上调。结论:钟基因Period2在肝癌中高表达，其作用与促进肝癌细胞Warburg效应，促进转移侵袭有关。

关键词: 生物钟基因, 癌, 肝细胞, warburg效应, 转移, 侵袭

Abstract:

AIM: To study the effects of circadian clock gene Period2 on Warburg effect and metastasis in hepatocellular carcinoma cells. METHODS: Real-time fluorescence quantitative PCR (RT-QPCR) was used to detect the expression of Period2 in tissues and 4 hepatocellular carcinoma cells,up-regulated the expression of Period2 in hepatocellular carcinoma cell line MHCC97L.silenced the expression of Period2 in hepatocellular carcinoma cell line HepG2.The glucose uptake level,lactic acid level，cell oxygen consumption level，cell viability，migration,and cell invasion were detected.Western-Blot was used to detect the expression of the key metabolic enzymes.RESULTS:The expression level of Period2 in MHCC97L was low,while HepG2 level was high.After Period2 silencing, the relative glucose uptake and lactate production of HepG2 cells were down-regulated compared with control group, and the oxygen consumption of HepG2 cells was increased compared with control,and the cell viability, migration and invasion ability were decreased.The expression level of key enzymes of glycometabolism was down-regulated.After overexpression of Period2,the glucose uptake level of MHCC97L cells was increased,the lactate production level was increased,the oxygen consumption was decreased compared with control, and the cell viability, migration and invasiveness were increased.The expression level of key enzymes of glucose metabolism was up-regulated.CONCLUSION: The clock gene Period2 is highly expressed in HCC, and its role is related to the promotion of Warburg effect and metastasis and invasion of HCC cells.

Key words: clock gene, cancer, Hepatocyte, Warburg effect, metastasis, invasion

中图分类号:

赵巧素，叶桦，孙勤学. 生物钟基因Period2调节肝癌细胞warburg效应及转移侵袭中的作用机制[J]. 中国临床药理学与治疗学, 2019, 24(10): 1134-1141.

ZHAO Qiaosu，YE Hua，SUN Qinxue. Effects of circadian clock gene Period2 on Warburg effect and metastasis in hepatocellular carcinoma cells[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(10): 1134-1141.

参考文献

［1］Benna C,Helfrich-Frster C,Rajendran S,et al.Genetic variation of clock genes and cancer risk:a field synopsis and meta-analysis［J］.Oncotarget,2017,8(14):23978-23995.
［2］Dudek M,Gossan N,Yang N,et al.The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity［J］.J Clin Invest,2016,126(1):365-372.
［3］Miki T,Matsumoto T,Zhao Z,et al.p53 regulates Period2 expression and the circadian clock［J］.Nat Commun，2013,4(9):2444.
［4］Gotoh T,Vilacaballer M,Santos CS,et al.The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells［J］.Mol Biol Cell，2014,25(19):3081-3093.
［5］Verneaux V,Jouvenot M,Compagnone P,et al.Expression of c-fos and c-myc genes in uterus and nonreproductive organs during the implantation period in the rat.［J］.Biochem Cell Biol，1992, 70(2):142-148.
［6］Li X,Yu X,Dong D,et al.The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters［J］.Oncotarget,2016,7(17):23141-23155.
［7］Tambe Y,Hasebe M,Kim CJ,et al.The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase-B［J］.Mol Carcinog，2016,55(1):52-63.
［8］Bosch F X,Ribes J,Díaz M,et al.Primary liver cancer:Worldwide incidence and trends［J］.Gastroenterology,2004,127(5):S5-S16.
［9］Savic LJ,Chapiro J,Duwe G,et al.Targeting glucose metabolism in cancer:new class of agents for loco-regional and systemic therapy of liver cancer and beyond［J］?Hepat Oncol,2016,3(1):19-28.
［10］Hsu PP,Sabatini DM.Cancer cell metabolism: Warburg and beyond［J］.Cell,2008,134(5):703-707.
［11］Wei H,Guo L,Li L,et al.Mechanism of Warburg effect and its effect on tumor metastasis［J］.Zhong guo Fei Ai Za Zhi，2015，18(3):179-183.
［12］Hardie DG,Alessi DR.LKB1 and AMPK and the cancer-metabolism link-ten years after［J］.Bmc Biology,2013,11(1):36.
［13］Tanaka T,Ikegami Y,Nakazawa H，et al.Low-dose farnesyltransferase inhibitor suppresses hif-1α and snail expression in triple-negative breast cancer MDA-MB-231 cells in vitro［J］.J Cell Physiol，2016,232(1):192-201.
［14］王瑾，杨毅，郭丽，等.普罗布考通过调节肝癌细胞HepG2代谢重编程逆转Warburg效应抑制其转移和侵袭的机制研究［J］.中国临床药理学与治疗学,2018,23(6):601-607.

[1]	游蓉丽, 黄玉荣, 毛睿, 海丽娜, 王颖莉, 王艳. 基于血清代谢组学与网络药理学探究复方苦参注射液治疗肺癌的作用机制[J]. 中国临床药理学与治疗学, 2023, 28(9): 988-999.
[2]	何李华, 朱秀之, 江一舟. 三阴性乳腺癌免疫治疗研究进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 842-853.
[3]	张胡云龙, 朱秀之, 金希, 邵志敏. 腔面型乳腺癌内分泌治疗耐药的机制与治疗进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 854-865.
[4]	付晓玉, 孔德光, 李娟娟. 三阳性乳腺癌的治疗进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 866-875.
[5]	罗师萍, 张捷, 俞育帅, 宋传贵. HER2阳性乳腺癌的靶向治疗进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 876-886.
[6]	向奕玫, 张宁宁, 黄雨昕, 曾晓华. HER2阳性乳腺癌疗效相关生物标志物研究进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 887-897.
[7]	陈柯羽, 黄圆, 王晓稼, 郑亚兵. 抗体偶联药物在乳腺癌中的临床应用与研究进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 898-909.
[8]	李梦茜, 张克兢, 夏凡. 乳腺癌疫苗研究进展[J]. 中国临床药理学与治疗学, 2023, 28(8): 918-925.
[9]	张景惠, 卫浩亮, 王丽, 李京凯, 张宝来, 杨孝来. AMI-1通过下调PRMT5表达对胰腺癌细胞体外活性的影响[J]. 中国临床药理学与治疗学, 2023, 28(6): 601-608.
[10]	付婷, 李芳, 潘大燕, 夏园园, 张秋园. 肺癌细胞外泌体来源的miR-718通过靶向PTEN诱导血管新生的研究[J]. 中国临床药理学与治疗学, 2023, 28(6): 624-632.
[11]	王艳, 张金辉, 赵永辰, 刘宏祥, 刘亚维, 苗欢欢, 杨信才. 红杉黄酮通过下调PI3K/AKT信号通路抑制胃癌细胞增殖侵袭等干细胞特性[J]. 中国临床药理学与治疗学, 2023, 28(5): 508-513.
[12]	封壮壮, 宋瑞平, 豆鹏程, 陈心怡, 左娇娇, 舒劲. 基于mTOR/Beclin1/LC3信号轴探讨制萎扶胃丸对胃癌前病变大鼠胃窦组织自噬的影响[J]. 中国临床药理学与治疗学, 2023, 28(4): 361-370.
[13]	石大伟, 郑晓永, 靳晓丹, 赵晓曼, 陈杰, 杜幸军. XPC基因多态性rs2228001对接受卡培他滨为基础辅助化疗的结直肠癌患者预后的影响[J]. 中国临床药理学与治疗学, 2023, 28(4): 391-399.
[14]	周晶, 周琛, 廖珂, 邱爱林, 董巍檑, 郭紫芬. 孕激素受体基因G1978T 多态性与子宫内膜癌的相关性研究[J]. 中国临床药理学与治疗学, 2023, 28(4): 400-406.
[15]	何杨, 杨魁, 栾家杰. CDA-G208A基因多态性对吉西他滨一线治疗肺鳞癌的疗效影响[J]. 中国临床药理学与治疗学, 2023, 28(3): 299-306.

生物钟基因Period2调节肝癌细胞warburg效应及转移侵袭中的作用机制

Effects of circadian clock gene Period2 on Warburg effect and metastasis in hepatocellular carcinoma cells

PDF (PC)

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