Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor.
Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor.
复制标题
删除内皮细胞特异性肝激酶 B1 可通过血管内皮生长因子增加血管生成和肿瘤生长。
作者：
Zhang W;Ding Y;Zhang C;Lu Q;Liu Z;Coughlan K;Okon I;Zou MH
肝激酶B1 （LKB1）是一种在哺乳动物细胞中普遍表达的丝氨酸/苏氨酸蛋白激酶。它最初是在Peutz-Jeghers综合征中作为肿瘤抑制基因被发现的。内皮细胞LKB1是否调节血管生成和肿瘤生长尚不清楚。在这项研究中，我们通过血管内皮-钙粘蛋白- cre小鼠与LKB1flox/flox小鼠杂交，产生了内皮细胞特异性lkb1敲除（LKB1endo - / -）小鼠。血管内皮生长因子（VEGF）水平在LKB1endo−/−小鼠的内皮细胞中高度共染，而在巨噬细胞中没有。一致地，LKB1endo - / -小鼠组织包括肺、皮肤、肾脏和肝脏显示血管通透性增加。与野生型小鼠相比，植入LKB1endo - / -小鼠而非巨噬细胞特异性lkb1敲除小鼠的肿瘤生长更快，血管通透性增强，血管新生增加。在体内注射vegf中和抗体而非同型匹配对照抗体可降低内皮细胞血管生成和肿瘤生长。此外，LKB1缺失增强了小鼠视网膜和细胞的血管生成，通过小干扰RNA敲低VEGF降低了内皮细胞的增殖和迁移。重新表达LKB1或敲低VEGF受体2可减少LKB1endo−/−细胞的过度增殖和迁移。机制上，LKB1可以结合VEGF转录因子特异性蛋白1 (Sp1)，抑制Sp1与VEGF启动子的结合，从而降低VEGF的表达。内皮细胞LKB1可能通过调节sp1介导的VEGF表达来调节内皮血管生成和肿瘤生长。
Liver kinase B1 (LKB1) is a serine/threonine protein kinase ubiquitously expressed in mammalian cells. It was first identified in Peutz-Jeghers syndrome as a tumor suppressor gene. Whether endothelial LKB1 regulates angiogenesis and tumor growth is unknown. In this study, we generated endothelial cell-specific LKB1-knockout (LKB1endo−/−) mice by crossbreeding vascular endothelial-cadherin-Cre mice with LKB1flox/flox mice. Vascular endothelial growth factor (VEGF) level was highly co-stained in endothelial cells but not macrophages in LKB1endo−/− mice. Consistently, LKB1endo−/− mouse tissues including the lung, skin, kidney, and liver showed increased vascular permeability. Tumors implanted in LKB1endo−/− mice but not macrophage-specific LKB1-knockout mice grew faster and showed enhanced vascular permeability and increased angiogenesis as compared with those implanted in wild-type mice. Injection of VEGF-neutralizing antibody but not the isotype-matched control antibody decreased endothelial-cell angiogenesis and tumor growth in vivo. Furthermore, LKB1 deletion enhanced mouse retinal and cell angiogenesis, and knockdown of VEGF by small-interfering RNA decreased endothelial cell proliferation and migration. Re-expression of LKB1 or knockdown of VEGF receptor 2 decreased the over-proliferation and -migration observed in LKB1endo−/− cells. Mechanistically, LKB1 could bind to the VEGF transcription factor, specificity protein 1 (Sp1), which then inhibited the binding of Sp1 to the VEGF promoter to reduce VEGF expression. Endothelial LKB1 may regulate endothelial angiogenesis and tumor growth by modulating Sp1-mediated VEGF expression.
登录
查看更多内容
影响因子：
15.9
作者：
Pasula, Satish;Cai, Xiaofeng;Chen, Hong
通讯作者：
Chen, Hong
影响因子：
5.3
作者：
Xie, Zhonglin;Dong, Yunzhou;Zou, Ming-Hui
通讯作者：
Zou, Ming-Hui
LKB1抑制肺癌细胞侵袭是由于组织因子和血管内皮生长因子的下调，部分依赖于SP1
影响因子：
5.2
作者：
Liang, Xuan;Li, Zhao-Lun;Nan, Ke-Jun
通讯作者：
Nan, Ke-Jun
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
78.5
作者：
Shackelford, David B.;Shaw, Reuben J.
通讯作者：
Shaw, Reuben J.