Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF
Authors: Bjorn R Olsen
Damian Medici
Journal: PLoS ONE (2012)
Discipline: Multidisciplinary
Keywords: Hemangiomas; Vascular endothelial cells; VEGF; VEGFR2; mTOR inhibitor
Affiliations: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America. 

Abstract:  Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1). VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas. 

Retracted: Yes

PubPeer comments:
 2020 retraction https: journals.plos.org plosone article?id=10.1371 journal.pone.0234141 Following publication of this article [1], concerns were raised about Fig 5 and Supporting Information S1 Fig. Specifically: The p70S6K panel in Fig 5A in [1] appears similar to Fig 2C, VE-cadherin panel, lanes 1u20134, in [2]. The corresponding author stated that an error was made in preparing Fig 2C of [2] and that Fig 5A of [1] reports the correct data. u03b2-actin panel lanes 4u20136 in S1 Fig of [1] appear similar to Fig 1, FHs74Int Iu03baB panel, lanes 1u20133 in [3], with aspect ratio adjusted. The corresponding author stated that these panels show different images, and further commented that the result in S1 Fig was confirmed in Fig 1A of [1]. Harvard Medical School, Harvard School of Dental Medicine, and Beth Israel Deaconess Medical Center reviewed concerns about certain data reported in this article, confirmed the above issues, and noted that the corresponding author did not identify reliable primary data to support the results. Harvard Medical School, Harvard School of Dental Medicine, and Beth Israel Deaconess Medical Center recommended retraction of the PLOS ONE article. The corresponding author provided electronic images of blots and laboratory records relevant to the panels in question, but the files provided did not resolve the above issues and were not sufficient to support the results of the entire experiment represented in each figure. The corresponding author said he cannot provide the original raw data supporting Fig 5A, S1 Fig, and other results reported in this article because he no longer has access to it. He said that the raw data files were stored on laboratory computers at Beth Israel Deaconess Medical Center when he (DM) left the institution in 2012. In light of the above concerns and in line with the institutionsu2019 recommendation, the PLOS ONE Editors retract this article. BRO did not agree with retraction. DM did not agree with retraction, noted that he stands by all findings and conclusions reported in this article, and said that he has initiated further actions in response to this case. The p70S6K panel of Fig 5A is similar to material from [2], published in 2011 by Biochemical Society, which is not offered under a CC-BY license. The u03b2-actin panel in S1 Fig includes content similar to material in [3], published in 2008 by The Rockefeller University Press and made available under a CC BY-NC-SA 3.0 license six months after publication. The p70S6K panel of Fig 5A and the u03b2-actin panel of S1 Fig are therefore excluded from this articleu2019s [1] license. At the time of retraction, the article [1] was republished to note these exclusions in the figure legends and the articleu2019s copyright statement. References 1.Medici D, Olsen BR (2012) Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF. PLoS ONE 7(8): e42913. https: doi.org 10.1371 journal.pone.0042913 2.Medici D, Potenta S, Kalluri R. (2011) Transforming growth factor-u03b22 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem J. 437(3):515u201320. pmid:21585337 3.Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B. (2008) FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. J Cell Biol. 182(3):459u201365. pmid:18678710 ,