title: Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor.
abstract: 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/floxmice. Vascular endothelial growth factor (VEGF) level was highly co-stained in endothelial cells but not in 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 overproliferation 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.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center of Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center of Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Center of Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Section of Molecule Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: K
authors.initials: K
authors.lastname: Coughlan
authors.affiliation: Center of Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Okon
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China.|Center of Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA.
authors.forename: M-H
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases