Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of Cyclins A and E.
Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of Cyclins A and E.
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DOI：
10.1053/j.gastro.2012.02.049
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发表时间：
2012-06
期刊：
影响因子：
29.4
通讯作者：
Ma C
中科院分区：
文献类型：
--
作者：
Yue X;Zhang Z;Liang X;Gao L;Zhang X;Zhao D;Liu X;Ma H;Guo M;Spear BT;Gong Y;Ma C
锌指和同源盒2 （ZHX2）抑制几种与肝癌相关的基因的转录。然而，关于ZHX2在肝细胞癌（HCC）发展中的作用知之甚少。我们研究了ZHX2可能影响HCC细胞增殖的机制。我们在HCC细胞中过表达和敲低ZHX2，并分析其对细胞增殖、集落形成和细胞周期的影响。我们还分析了ZHX2过表达对HepG2.2.15异种肿瘤裸鼠生长的影响。采用染色质免疫沉淀法和荧光素酶报告基因法测定ZHX2靶启动子的结合情况。免疫组化法检测肝癌组织中ZHX2的表达水平。ZHX2过表达可显著降低小鼠肝癌细胞增殖和肿瘤移植物生长；它导致HCC细胞系中G1阻滞和细胞周期蛋白A和E水平降低。ZHX2结合CCNA2（编码细胞周期蛋白A）和CCNE1（编码细胞周期蛋白E）的启动子区域，抑制它们的转录。敲低细胞周期蛋白A或细胞周期蛋白E可降低ZHX2敲低介导的增殖增加。在培养细胞和小鼠体内抑制肝癌细胞增殖需要ZHX2的核定位。与邻近的非肿瘤组织相比，人类HCC样本中，即使在小肿瘤（直径<5 cm）中，ZHX2的核定位也降低。此外，ZHX2核水平降低与患者生存时间缩短、肿瘤微血管化水平升高和肝细胞增殖相关。ZHX2通过抑制细胞周期蛋白A和E的表达抑制肝癌细胞增殖，降低小鼠异种移植肿瘤的生长。核ZHX2的缺失可能是HCC发展的早期阶段。
Zinc-fingers and homeoboxes 2 (ZHX2) represses transcription of several genes associated with liver cancer. However, little is known about the role of ZHX2 in development of hepatocellular carcinoma (HCC). We investigated the mechanisms by which ZHX2 might affect proliferation of HCC cells. We overexpressed and knocked down ZHX2 in HCC cells and analyzed the effects on proliferation, colony formation, and the cell cycle. We also analyzed the effects of ZHX2 overexpression in growth of HepG2.2.15 tumor xenografts in nude mice. Chromatin immunoprecipitation and luciferase reporter assays were used to measure binding of ZHX2 target promoters. Levels of ZHX2 in HCC samples were evaluated by immunohistochemistry. ZHX2 overexpression significantly reduced proliferation of HCC cells and growth of tumor xenografts in mice; it led to G1 arrest and reduced levels of cyclins A and E in HCC cell lines. ZHX2 bound to promoter regions of CCNA2 (which encodes Cyclin A) and CCNE1 (which encodes cyclin E) and inhibited their transcription. Knockdown of cyclin A or cyclin E reduced the increased proliferation mediated by ZHX2 knockdown. Nuclear localization of ZHX2 was required for it to inhibit proliferation of HCC cells in culture and in mice. Nuclear localization of ZHX2 was reduced in human HCC samples, even in small tumors (diameter<5 cm), compared to adjacent non-tumor tissues. Moreover, reduced nuclear levels of ZHX2 correlated with reduced survival times of patients, high levels of tumor microvascularization, and hepatocyte proliferation. ZHX2 inhibits HCC cell proliferation, by preventing expression of cyclins A and E, and reduces growth of xenograft tumors in mice. Loss of nuclear ZHX2 might be an early step in the development of HCC.
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影响因子：
3
作者：
Legartova, S.;Harnicarova-Horakova, A.;Kozubek, S.
通讯作者：
Kozubek, S.
影响因子：
14.5
作者：
Abelev, GI;Eraiser, TL
通讯作者：
Eraiser, TL
DOI：
10.1161/circgenetics.109.902320
发表时间：
2010-02
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Gargalovic PS;Erbilgin A;Kohannim O;Pagnon J;Wang X;Castellani L;LeBoeuf R;Peterson ML;Spear BT;Lusis AJ
通讯作者：
Lusis AJ
影响因子：
9.7
作者：
Jung, YJ;Lee, KH;Kim, CM
通讯作者：
Kim, CM
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR