Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer.
Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer.
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DOI：
10.1016/j.taap.2012.07.019
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发表时间：
2012-10-01
影响因子：
3.8
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Yu, Wei;Chai, Hongyan;Li, Ying;Zhao, Haixia;Xie, Xianfei;Zheng, Hao;Wang, Chenlong;Wang, Xue;Yang, Guifang;Cai, Xiaojun;Falck, John R.;Yang, Jing
细胞色素P450（CYP 4）4 Z1是CYP 4家族的新成员，在乳腺癌中过度表达，与高级别肿瘤和不良预后相关。然而，CYP 4 Z1在肿瘤进展中的确切作用尚不清楚。在这里，我们证明CYP 4 Z1过表达促进乳腺癌的肿瘤血管生成和生长。CYP 4 Z1在T47 D和BT-474人乳腺癌细胞中的稳定表达显著增加了血管内皮生长因子（VEGF）-A的mRNA表达和产生，并降低了金属蛋白酶组织抑制剂-2（TIMP-2）的mRNA水平和分泌，而不影响细胞增殖和锚定非依赖性细胞生长。值得注意的是，来自CYP 4 Z1表达细胞的条件培养基增强了人脐静脉内皮细胞的增殖、迁移和管形成，并促进了斑马鱼胚胎和鸡胚绒毛尿囊膜中的血管生成。此外，与载体对照相比，表达CYP 4 Z1的T47 D细胞中肉豆蔻酸和月桂酸的水平较低，而20-羟基二十碳四烯酸（20-HETE）的含量较高。在人类肿瘤异种移植模型中，CYP 4 Z 1过表达使肿瘤重量和微血管密度分别显着增加2.6倍和1.9倍。此外，CYP 4 Z1转染增加了ERK 1/2和PI 3 K/Akt的磷酸化，而PI 3 K或ERK抑制剂和siRNA沉默逆转了CYP 4 Z1介导的VEGF-A和TIMP-2表达的变化。相反，CYP 4家族抑制剂HET 0016有效抑制肿瘤诱导的血管生成，并伴随肉豆蔻酸、月桂酸和20-HETE细胞内水平的相关变化。总的来说，这些数据表明，CYP 4 Z 1表达增加部分通过PI 3 K/Akt和ERK 1/2激活促进乳腺癌的肿瘤血管生成和生长。
Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation.
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DOI：
10.1083/jcb.200409115
发表时间：
2005-05-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee S;Jilani SM;Nikolova GV;Carpizo D;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
4.8
作者：
Connor, KM;Subbaram, S;Melendez, JA
通讯作者：
Melendez, JA
DOI：
10.1152/ajpheart.01087.2008
发表时间：
2009-03-01
影响因子：
4.8
作者：
Dhanasekaran, Anuradha;Bodiga, Sreedhar;Jacobs, Elizabeth R.
通讯作者：
Jacobs, Elizabeth R.
影响因子：
14.5
作者：
Bourboulia D;Stetler-Stevenson WG
通讯作者：
Stetler-Stevenson WG
DOI：
10.1124/jpet.105.088567
发表时间：
2005-11-01
影响因子：
3.5
作者：
Guo, M;Roman, RJ;Scicli, AG
通讯作者：
Scicli, AG