Recent evidence indicates that endothelial cell via angiocrine factors promote tumor growth and metastasis. Understanding how excessive amount of angiocrine factors are produced and how they influence tumor development might unveil novel targets for therapies. Our exciting preliminary data demonstrates Liver Kinase B1 (LKB1), a tumor suppressor gene, regulates Neuropilin (NRP)-1 and VEGF, suggesting that LKB1 may be a central mediator of angiogenesis and tumor growth through its inhibitory function on NRP-1 and VEGF. The central hypothesis of this application is that LKB1 in both ECs and tumor cells down-regulates NRP-1 and other pro-angiogenic factors (PDGF & FGFR) while inhibiting Sp1-induced VEGF transcriptional activation thereby maintaining a state of suppressed angiogenesis and tumor growth. There are three interrelated aims to validate or to refute this hypothesis.
Aim 1 is to establish if LKB1 leads to decreased VEGF expression through impeding transcriptional activation hence altering physiological angiogenesis.
Aim 2 is to establish if LKB1 suppresses NRP-1 and other non-VEGF growth factors-mediated angiogenesis. Finally, in Aim 3, we will determine the contribution of LKB1 down-regulation of VEGF and NRP-1 within the vascular niche in vivo. We fully anticipate the completion of this project will help define the molecular mechanism by which LKB1 suppresses transcriptional expression and activity of VEGF, NRP-1, and other pro-angiogenic factors (FGFR & PDGFR) within the vascular niche resulting in a reduction in tumor growth and ischemic angiogenesis.

Public Health Relevance

The overall goal of this project is to define the molecular mechanism by which LKB1 enhances NRP-1 degradation and suppresses transcriptional expression of VEGF thereby leading to aberrant signaling within the vascular niche resulting in a reduction in tumor growth and ischemic angiogenesis. .

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA213022-02
Application #
9394792
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Snyderwine, Elizabeth G
Project Start
2016-12-07
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Georgia State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Dai, Xiaoyan; Okon, Imoh; Liu, Zhaoyu et al. (2017) A novel role for myeloid cell-specific neuropilin 1 in mitigating sepsis. FASEB J 31:2881-2892
Lu, Qiulun; Xie, Zhonglin; Yan, Chenghui et al. (2017) Snf1 (Sucrose Nonfermenting 1)-Related Kinase Promotes Angiogenesis In Vivo. Arterioscler Thromb Vasc Biol :
Wang, Qiongxin; Ding, Ye; Song, Ping et al. (2017) Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo. Circulation 136:2271-2283
Liu, Zhaoyu; Zhu, Huaiping; Dai, Xiaoyan et al. (2017) Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis. Circ Res 121:1047-1057
Okon, Imoh; Ding, Ye; Zou, Ming-Hui (2017) Ablation of Interferon Regulatory Factor 3 Promotes the Stability of Atherosclerotic Plaques. Hypertension 69:407-408
Duan, Quanlu; Song, Ping; Ding, Ye et al. (2017) Activation of AMP-activated protein kinase by metformin ablates angiotensin II-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br J Pharmacol 174:2140-2151
Song, Ping; Ramprasath, Tharmarajan; Wang, Huan et al. (2017) Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell Mol Life Sci 74:2899-2916
Dai, Xiaoyan; Okon, Imoh; Liu, Zhaoyu et al. (2017) Ablation of Neuropilin 1 in Myeloid Cells Exacerbates High-Fat Diet-Induced Insulin Resistance Through Nlrp3 Inflammasome In Vivo. Diabetes 66:2424-2435
Zhang, W; Ding, Y; Zhang, C et al. (2017) Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor. Oncogene 36:4277-4287
Ding, Ye; Zou, Ming-Hui (2017) AMP-Activated Protein Kinase ?2 to the Rescue in Ischemic Heart. Circ Res 121:1113-1115

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