Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor
Authors: Aleem Siddiqui
Md Nasimuzzaman
David Mikolon
Gulam Waris
Dwayne G Stupack
Journal: Journal of Virology (2007)
Discipline: MICROBIOLOGY
Keywords: Hepatitis C virus; HCV gene expression; angiogenesis; hypoxia-inducible factor 1alpha; oxidative stress
Affiliations: Department of Medicine, Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0711, Department of Pathology and Moore's Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, California 92093-0803

Abstract:  Hepatitis C virus (HCV) infection is one of the major causes of chronic hepatitis, liver cirrhosis, which subsequently leads to hepatocellular carcinoma (HCC). The overexpression of the angiogenic factors has been demonstrated in HCC. In this study, we investigated the potential of HCV gene expression in inducing angiogenesis. Our results show that HCV infection leads to the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha). We further show that this stabilization was mediated via oxidative stress induced by HCV gene expression. The activation of NF-kappaB, STAT-3, PI3-K/AkT, and p42/44 mitogen-activated protein kinase was necessary for HIF-1alpha stabilization. HIF-1alpha induction in turn led to the stimulation of vascular endothelial growth factor. By using the chick chorioallantoic membrane assay, we show that HCV-infected cells released angiogenic cytokines, leading to neovascularization in vivo. These results indicate the potential of HCV gene expression in angiogenesis. 

Retracted: Yes

PubPeer comments:
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 Figure 1C. https: imgur.com UQw3Fs4 , 
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 Retraction Watch discussion of concerns about co-author Waris here: https: retractionwatch.com 2019 08 22 hepatitis-expert-up-to-five-retractions-and-one-expression-of-concern-denies-reusing-images Journals seem to be very slow in responding to these image concerns. , 
 I think the 2018 retraction withdrawal of G. Waris, et.al., J Biol Chem (2003) included the paper here in the list of papers in which they found figure reuse (see bold below) http: www.jbc.org content 293 52 20012 u201cThis article has been withdrawn by the authors. Antonia Livolsi, Vu00e9ronique Imbert, and Jean-Franu00e7ois Peyron participated in the study by providing Iu03baBu03b1 mutant plasmids. An investigation by the Journal determined the following. A band was pasted over in the NS5A immunoblot in Fig. 2A. The actin immunoblot from Fig. 2A was reused as actin in 2B, NS5A in 4A, NS5A in 4B, actin in 7D, and actin in 9A. Additionally, this actin immunoblot was reused in the following publications representing different experimental conditions: Waris et al. (2005) J. Virol. 79, 1569u20131580, Waris and Siddiqui (2005) J. Virol. 79, 9725u20139734, Waris et al. (2007) J. Virol. 81, 8122u20138130, **Nasimuzzaman et al. (2007) J. Virol. 81, 10249u201310257**, Burdette et al. (2010) J. Gen. Virol. 91, 681u2013690, Burdette et al. (2012) J. Gen. Virol. 93, 235u2013246, Presser et al. (2013) PLOS One 8, e56367, and McRae et al. (2016) J. Biol. Chem. 291, 3254u20133267. The EMSA shown in Fig. 3D was reused in Waris et al. (2005) J. Virol. 79, 1569u20131580 representing different experimental conditions. Lanes 3 and 5 of the Iu03baBu03b1 immunoblot in Fig. 9A were duplicated. The authors who performed the experiments were unable to clarify the Journal s concerns with original data. Gulam **Waris does not agree that the actin immunoblot was reused in other publications.** Aleem Siddiqui disagrees with the determination of the reuse of actin immunoblots in publications other than the JBC paper being withdrawn. The authors sincerely apologize to the readers.u201d , 
 2020 retraction this paper. https: jvi.asm.org content 94 19 e01403-20 Volume 81, no. 19, p. 10249u201310257, 2007, https: doi.org 10.1128 JVI.00763-07. It has been called to our attention that the actin bands from Fig. 2A in Journal of Biological Chemistry 278:40778u201340787, 2003, https: doi.org 10.1074 jbc.M303248200 (article retracted), were reused in Fig. 1C and 4B. The HCV core blot in Fig. 4B is reused in Fig. 6A in Journal of General Virology 93(2):235u2013246, 2012, https: doi.org 10.1099 vir.0.034033-0 (article retracted), as a NALP3 band. Unfortunately, the laboratory no longer has the original data nor the corresponding lab notes. Under the circumstances, we retract this paper. ,