乙型肝炎病毒X蛋白上调环加氧酶2表达促进肝癌细胞增殖的实验研究X Protein of the Hepatitis B Virus Promotes the Proliferation of Hepatoma Cells by Upregulating Cyclooxygenase-2 Expression:An Experimental Study
元顺女;朴美花;金丹;
摘要(Abstract):
乙肝病毒X蛋白(Hepatitis B virus X protein,HBx)高表达与乙肝相关肝癌的发病密切相关,但HBx发挥促癌作用的机制并不清楚。环加氧酶2(Cyclooxygenase,COX2)具有促进肝癌细胞增殖的功能,乙肝相关肝癌中COX2的表达增加且与HBx呈正相关,提示上调COX2可能是HBx促进肝癌细胞增殖的分子机制。为了阐明HBx是否通过上调COX2促进肝癌细胞增殖,本实验培养了肝癌HepG2细胞并分为对照组、转染pcDNA3.1-HBx质粒的HBx组、转染NC siRNA的si-NC组、转染NC siRNA及pcDNA3.1-HBx质粒的si-NC+HBx组、转染COX2 siRNA及pcDNA3.1-HBx质粒的si-COX2+HBx组。检测细胞增殖活力OD_(490nm)的水平,COX2、B淋巴细胞瘤2基因(BCL2)、生存素(Survivin)的表达量,前列腺素E2(英文名,PGE2)的含量。实验结果显示,HBx组的OD_(490nm)水平,细胞中COX2、BCL2、Survivin的表达量,培养基中PGE2的含量均高于对照组;si-COX2+HBx组的OD_(490nm)水平,细胞中COX2、BCL2、Survivin的表达量,培养基中PGE2的含量均低于si-NC+HBx组。以上结果表明,HBx促进肝癌细胞增殖的作用部分由上调COX2表达所介导。本实验阐明了上调COX2在HBx促进肝癌细胞增殖中的作用,这为今后研究HBx发挥促癌作用的分子机制以及乙肝相关肝癌的发病机制提供了新思路。
关键词(KeyWords): 乙肝相关肝癌;乙肝病毒X蛋白(HBx);环氧合酶2(COX2);前列腺素E2(PGE2);细胞增殖
基金项目(Foundation):
作者(Authors): 元顺女;朴美花;金丹;
DOI: 10.13242/j.cnki.bingduxuebao.004042
参考文献(References):
- [1] Jindal A, Thadi A, Shailubhai K. Hepatocellular carcinoma:Etiology and current and future drugs[J]. J Clin Exp Hepatol,2019,9(2):221-232.
- [2] Chen W,Huang L,Liu H,Li XM,Xu CM.Expressions of HBV X gene regulated by different promoters and their effects on cell apoptosis[J]. Eur Rev Med Pharmacol Sci,2018,22(18):5906-5913.
- [3] Jegal ME,Jung SY,Han YS,Kim YJ. C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells[J]. BMB Rep,2019,52(5):330-335.
- [4] Deng L,Liang H,Han Y. Cyclooxygenase-2 and β-Catenin as potential diagnostic and prognostic markers in endometrial cancer[J]. Front Oncol,2020,21(10):56.
- [5] Zhang T,Wang Q,Ma WY,Wang K,Chang X,Johnson ML,Bai R,Bode AM,Foster NR,Falk GW,Limburg PJ,Iyer PG,Dong Z. Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development[J]. EBioMedicine,2019,49:145-156.
- [6] Xiao J,Wang F,Lu H,Xu S,Zou L,Tian Q,Fu Y,Lin X,Liu L,Yuan P,Ni X,Ma T,Zeng F,Xue P,Xiu R,Zhang J,Ji X,Hu H,Lu S,Dai H,Li Y,Chu Q,Zhao X,Duan Q,Zhu F. Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells[J]. Cell Death Dis,2019,10(10):777.
- [7]谢华红,张勇.环加氧酶2(Cox-2)在乙型肝炎病毒相关性肝癌组织中高表达且与乙型肝炎病毒X(HBx)蛋白表达呈正相关[J].细胞与分子免疫学杂志,2018,34(10期):919-923.
- [8] Yen CJ,Yang ST,Chen RY,Huang W,Chayama K,Lee MH,Yang SJ,Lai HS,Yen HY,Hsiao YW,Wang JM, Lin YJ, Hung LY. Hepatitis B virus X protein(HBx)enhances centrosomal P4.1-associated protein(CPAP)expressiontopromote hepatocarcinogenesis[J]. J Biomed Sci, 2019,26(1):44.
- [9] Zha Y,Yao Q,Liu JS,Wang YY,Sun WM. Hepatitis B virus X protein promotes epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cell line HCCLM3 by targeting HMGA2[J]. Oncol Lett,2018,16(5):5709-5714.
- [10]张斌,丁慎华,徐春江,许智玲,朱薇珊. HBx过表达对肝癌HepG2细胞AKT、PI3K表达的影响[J].胃肠病学和肝病学杂志,2019,28(2):159-162.
- [11]Jia H,Wang H,Yao Y,Wang C,Li P. miR-136Inhibits malignant progression of hepatocellular carcinoma cells by targeting cyclooxygenase 2[J]. Oncol Res,2018,26(6):967-976.
- [12]Lv X, Chen Z, Li S, Xie H. Knockdown of cyclooxygenase-2 leads to growth inhibition and cell cycle arrest in hepatocellular carcinoma cells[J]. Onco Targets Ther,2019,31(12):4341-4349.
- [13]Dai H,Zhang S,Ma R,Pan L. Celecoxib inhibits hepatocellular carcinoma cell growth and migration by targeting PNO1[J]. Med Sci Monit,2019,30(25):7351-7360.
- [14]Tai Y,Zhang LH,Gao JH,Zhao C,Tong H,Ye C,Huang ZY,Liu R,Tang CW. Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2[J].Cancer Manag Res,2019,9(11):2831-2848.
- [15]Fang Q,Zhu Y,Wang Q,Song M,Gao G,Zhou Z.Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt-PI3K signaling pathway in lung cancer cells[J]. Int J Mol Med,2019,43(1):507-516.
- [16]Garrido MP,Hurtado I,Valenzuela-Valderrama M,Salvatierra R, Hernández A, Vega M, Selman A,Quest AFG,Romero C. NGF-enhanced vasculogenic properties of epithelial ovarian cancer cells is reduced by inhibition of the COX-2/PGE2 Signaling Axis[J/OL].Cancers(Basel),2019,11(12):e1970.
- [17]Lin XM,Luo W,Wang H,Li RZ,Huang YS,Chen LK,Wu XP. The role of prostaglandin-endoperoxide synthase-2 in chemoresistance of non-small cell lung cancer[J]. Front Pharmacol,2019,8(10):836.
- [18]Song S,Sun K,Dong J,Zhao Y,Liu F,Liu H,Sha Z,Mao J,Ding G,Guo W,Fu Z. microRNA-29a regulates liver tumor-initiating cells expansion via Bcl-2pathway[J]. Exp Cell Res,2020,387(2):111781.
- [19]Kapiris I,Nastos K,Karakatsanis A,Theodosopoulos T,Karandrea D,Kondi Pafiti A,Contis J. Survivin expression in hepatocellular carcinoma. Correlation with clinicopathological characteristics and overall survival[J]. J BUON,2019,24(5):1934-1942.
- [20]Namgung Y,Kim SY,Kim I. Down-regulation of survivin by BIX-01294 pretreatment overcomes resistance of hepatocellular carcinoma cells to TRAIL[J]. Anticancer Res,2019,39(7):3571-3578.