Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor

作者：Zhang, W.^*; Ding, Y.; Zhang, C.; Lu, Q.; Liu, Z.; Coughlan, K.; Okon, I.; Zou, M-H

来源：Oncogene, 2017, 36(30): 4277-4287.

DOI：10.1038/onc.2017.61

• PEUTZ-JEGHERS-SYNDROME
• FACTOR MESSENGER-RNA
• MICROVASCULAR PERMEABILITY
• SUPPRESSOR KINASE
• SPLICE VARIANT
• LKB1
• VEGF
• METABOLISM
• EXPRESSION
• INVASION

Liver kinase B1 (LKB1) is a serine/threonine protein kinase ubiquitously expressed in mammalian cells. It was first identified in PeutzJeghers 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 (LKB1(endo-/-)) mice by crossbreeding vascular endothelialcadherin-Cre mice with LKB1(flox/flox) mice. Vascular endothelial growth factor (VEGF) level was highly co-stained in endothelial cells but not in macrophages in LKB1(endo-/-) mice. Consistently, LKB1(endo-/-) mouse tissues including the lung, skin, kidney and liver showed increased vascular permeability. Tumors implanted in LKB1(endo-/-) mice but not macrophage-specific LKB1- knockout mice grew faster and showed enhanced vascular permeability and increased angiogenesis as compared with those implanted in wildtype 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 overproliferation and -migration observed in LKB1(endo-/-) 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.

• 出版日期2017-7-27
• 单位山东大学