Identification of the Fra-1 transcription factor in healing skin flaps transplants: A potential role as a negative regulator of VEGF release from keratinocytes

Seitz, Oliver; Schürmann, Christoph; Pfeilschifter, Josef; Frank, Stefan; Sader, Robert

doi:10.1016/j.jcms.2011.07.001

Cited by 5 publications

(2 citation statements)

References 41 publications

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“…In agreement with a previous study in epithelial cells (21), 50 ng/ml EGF was observed to augment Fra-1 protein levels in CIN cell nuclei (Fig. 1B).…”

Section: Resultssupporting

confidence: 93%

“…Another study demonstrated that the induction of MMP-9 expression by EGF in epithelial cells is preceded and/or accompanied by the phosphorylation and activation of signalling molecules, including the serine/threonine kinase AKT (20). EGF-induced phosphorylation of AKT leads to the activation of members of the activator protein-1 transcriptional complex, such as Fos-related antigen (Fra)-1 (21), which is a potent activator of MMP-9 gene expression (22–24). Notably, the E6 and E7 proteins of HR-HPV have been shown to phosphorylate AKT (25,26) and to promote MMP-9 expression (27,28).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of MMP-9 expression by ritonavir or saquinavir is associated with inactivation of the AKT/Fra-1 pathway in cervical intraepithelial neoplasia cells

Bacigalupo¹,

Palladino²,

Leone³

et al. 2017

Oncology Letters

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Abstract.A reduced incidence and decreased clinical progression of uterine cervical intraepithelial neoplasia (CIN) has been observed in women infected with human immunodeficiency virus (HIV) treated with HIV-protease inhibitors (PIs). The HIV-PIs saquinavir (SQV) and ritonavir (RTV) have been demonstrated to efficiently inhibit invasion of human primary CIN cells by downregulating the expression of matrix metalloproteinase (MMP)-9. The present study further investigated the molecular mechanisms underlying the activity of SQV and RTV in CIN. The results of the present study indicate that the treatment of human primary CIN cells with SQV or RTV directly impairs events leading to MMP-9 expression, including the phosphorylation of AKT and the nuclear localisation of the Fos-related antigen transcription factor. In addition, neither SQV nor RTV affected the expression of human papilloma virus proteins, such as E6 or E7. In view of the important role that the AKT/Fra-1/MMP-9 signalling pathway serves in CIN progression to invasive cervical carcinoma, these data further support the use of HIV-PIs in the treatment of CIN in women infected with HIV and women who are not infected with HIV. Furthermore, the present study identified a molecular mechanism underlying the anti-invasive effects of SQV/RTV, providing useful information for the development of SQV/RTV derivatives, which may be employed as novel anticancer drugs. IntroductionInfection of the uterine cervix by an oncogenic, high-risk (HR)-human papilloma virus (HPV) frequently results in low-grade cervical intraepithelial neoplasia (CIN), a dysplastic lesion that may progress into high-grade CIN and cervical carcinoma (1). The prevalence and persistence of HR-HPV, the incidence of CIN and the risk of CIN progression are high in women infected with HR-HPV and human immunodeficiency virus (HIV) (1). In these patients, antiretroviral drugs, including HIV-protease inhibitors (PIs), have reduced the rate of uterine CIN incidence and progression (2-4).The progression of CIN to invasive cervical carcinoma is initiated when HR-HPV + keratinocytes invade the basement membrane at the stromal/epithelial junction of the lesion (1). A previous study demonstrated that therapeutic concentrations of HIV-PIs, such as saquinavir (SQV) and ritonavir (RTV), effectively inhibit the invasive capabilities of HR-HPV + human primary keratinocytes obtained from low-grade CIN lesions (5). This inhibition of invasion was associated with the downregulation of the pro-invasive, basement membrane-degrading enzyme matrix metalloproteinase (MMP)-9 and, to a lesser extent, with the downregulation of MMP-2 (5). As these results were obtained in an in vitro experimental model devoid of HIV or immune cells, they confirm preclinical and clinical work indicating that HIV-PIs exert direct antitumour effects independently of their anti-HIV and/or immune reconstituting activities (5-14).The capability of SQV and RTV to inhibit the expression of MMP-9 has important implications, since MMP-9 serves a key ro...

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“…In agreement with a previous study in epithelial cells (21), 50 ng/ml EGF was observed to augment Fra-1 protein levels in CIN cell nuclei (Fig. 1B).…”

Section: Resultssupporting

confidence: 93%