The goal of this project is to investigate the molecular mechanisms by which the Myc oncoprotein enhances tumor neovascularization (the ingrowth of blood vessels into the nascent neoplasm). We have developed an experimental system wherein overexpression of this oncoprotein in murine colon carcinoma cells results in the hypervascular phenotype. We determined that this occurs without increased production of vascular endothelial growth factor (VEGF). Instead, Myc down-regulates the potent endogenous inhibitor of angiogenesis thrombospondin-1 and several other members of the TSR superfamily. Thrombospondin-1 is down-regulated primarily at the level of mRNA turnover, suggesting the involvement of microRNAs (miRNAs) which are known to mediate mRNA degradation. Indeed, Myc upregulates one of the miRNA clusters (miR17-92) whose predicted targets include thrombospondin-1 and other TSR proteins. miR17-92 knockdown with antisense 2'-O-methyl oligoribonucleotide partly restores Tsp1 and CTGF expression. Conversely, transduction of Ras-only cells with a miR17-92-encoding retrovirus reduces Tsp1 and CTGF levels. These key findings were also reproduced in HCT116 human colon carcinoma cells. Notably, miR17-92-transduced murine cells form larger, better-perfused tumors. Thus, we have formulated the following overall hypothesis: The contribution of Myc to tumor neovascularization is based on down-regulation of thrombospondin-1 and related proteins via a post-transcriptional mechanism involving the miR17-92 microRNA cluster. To corroborate this hypothesis, we propose to fulfill the following Specific Aims: 1. To dissect the molecular mechanisms underlying downregulation of TSR proteins by the miR17-92 cluster. 2. To establish the significance of Myc-dependent TSR protein down-regulation for neoplastic growth of Myc/Ras colonocytes and human colon cancer xenografts. 3. To elucidate the effects of transient Myc down-regulation on tumor vascularity and overall growth. After having fulfilled these Aims, we will be able to commence large-scale pre-clinical studies further validating miR17-92 and Myc as non-cell-autonomous therapeutic targets in vivo.
TO PUBLIC HEALTH: One of the promising anti-cancer drugs currently undergoing clinical trials is ABT-510. This drug mimics the effects of the natural tumor suppressor thrombospondin. Our research will help determine what types of colorectal cancer might be particularly sensitive to ABT-510 and allow for targeted patient enrollment. Additionally, our studies identify certain microRNAs as potential targets for anti-angiogenic therapies.
|Dews, Michael; Tan, Grace S; Hultine, Stacy et al. (2014) Masking epistasis between MYC and TGF-Î² pathways in antiangiogenesis-mediated colon cancer suppression. J Natl Cancer Inst 106:dju043|
|Psathas, James N; Thomas-Tikhonenko, Andrei (2014) MYC and the art of microRNA maintenance. Cold Spring Harb Perspect Med 4:|
|Psathas, James N; Doonan, Patrick J; Raman, Pichai et al. (2013) The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop. Blood 122:4220-9|
|Fox, Jamie L; Dews, Michael; Minn, Andy J et al. (2013) Targeting of TGFÃ½Ã½ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma. RNA 19:177-90|
|Hart, Lori S; Cunningham, John T; Datta, Tatini et al. (2012) ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest 122:4621-34|
|Zhang, Xiao-Yong; Pfeiffer, Harla K; Mellert, Hestia S et al. (2011) Inhibition of the single downstream target BAG1 activates the latent apoptotic potential of MYC. Mol Cell Biol 31:5037-45|
|Sotillo, Elena; Thomas-Tikhonenko, Andrei (2011) The long reach of noncoding RNAs. Nat Genet 43:616-7|
|Sundaram, Prema; Hultine, Stacy; Smith, Lauren M et al. (2011) p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. Cancer Res 71:7490-501|
|Sotillo, E; Laver, T; Mellert, H et al. (2011) Myc overexpression brings out unexpected antiapoptotic effects of miR-34a. Oncogene 30:2587-94|
|Sotillo, Elena; Thomas-Tikhonenko, Andrei (2011) Shielding the messenger (RNA): microRNA-based anticancer therapies. Pharmacol Ther 131:18-32|
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