U94 of human herpesvirus 6 down-modulates Src, promotes a partial mesenchymal-to-epithelial transition and inhibits tumor cell growth, invasion and metastasis

Caccuri, Francesca; Ronca, Roberto; Laimbacher, Andrea S.; Berenzi, Angiola; Steimberg, Nathalie; Campilongo, Federica; Mazzuca, Pietro; Giacomini, Arianna; Mazzoleni, Giovanna; Benetti, Anna; Caselli, Elisabetta; Presta, Marco; Luca, Dario Di; Fraefel, Cornel; Caruso, Arnaldo

doi:10.18632/oncotarget.17817

Cited by 12 publications

(22 citation statements)

References 48 publications

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“…HUVECs were isolated, characterized and cultured as previously described [58]. HMVEC-Ls were purchased from Clonetics (San Diego, CA, USA) and cultured in EGM-2MV (Lonza, Milan, Italy) containing 10% FBS.…”

Section: Cell Culturesmentioning

confidence: 99%

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Bugatti

Marsico

Mazzuca

et al. 2020

IJMS

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Although the advent of combined antiretroviral therapy has substantially improved the survival of HIV-1-infected individuals, non-AIDS-related diseases are becoming increasingly prevalent in HIV-1-infected patients. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications. Alterations in coagulation biology in the context of HIV infection seem to be largely a consequence of a chronically inflammatory microenvironment leading to endothelial cell (EC) dysfunction. A possible direct role of HIV-1 proteins in sustaining EC dysfunction has been postulated but not yet investigated. The HIV-1 matrix protein p17 (p17) is secreted from HIV-1-infected cells and is known to sustain inflammatory processes by activating ECs. The aim of this study was to investigate the possibility that p17-driven stimulation of human ECs is associated with increased production of critical coagulation factors. Here we show the involvement of autophagy in the p17-induced accumulation and secretion of von Willebrand factor (vWF) by ECs. In vivo experiments confirmed the capability of p17 to exert a potent pro-coagulant activity soon after its intravenous administration.

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Section: Cell Culturesmentioning

confidence: 99%

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Bugatti

Marsico

Mazzuca

et al. 2020

IJMS

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“…Of interest, the HHV-6A/B gene U94 exhibits anti-tumorigenic effects in some in-vitro carcinoma models. Expression of HHV-6B U94 in breast cancer and cervical cancer cell lines decreased the migration and invasiveness of the cells in vitro , and the injection of U94-expressing cancer cells into mice resulted in reduced tumor growth and more limited vasculature in the resulting tumors ( 173 ). Earlier, HHV-6A was found to reduce lymphangiogenesis and angiogenesis in vitro ( 174 ) and limit migration of endothelial cells ( 174 ) and oligodendrocyte progenitor cells ( 175 ).…”

Section: Potential Mechanisms Of Hhv-6-associated Neoplasiamentioning

confidence: 99%

Human Herpesvirus 6 and Malignancy: A Review

et al. 2018

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In order to determine the role of human herpesvirus 6 (HHV-6) in human disease, several confounding factors, including methods of detection, types of controls, and the ubiquitous nature of the virus, must be considered. This is particularly problematic in the case of cancer, in which rates of detection vary greatly among studies. To determine what part, if any, HHV-6 plays in oncogenesis, a review of the literature was performed. There is evidence that HHV-6 is present in certain types of cancer; however, detection of the virus within tumor cells is insufficient for assigning a direct role of HHV-6 in tumorigenesis. Findings supportive of a causal role for a virus in cancer include presence of the virus in a large proportion of cases, presence of the virus in most tumor cells, and virus-induced in-vitro cell transformation. HHV-6, if not directly oncogenic, may act as a contributory factor that indirectly enhances tumor cell growth, in some cases by cooperation with other viruses. Another possibility is that HHV-6 may merely be an opportunistic virus that thrives in the immunodeficient tumor microenvironment. Although many studies have been carried out, it is still premature to definitively implicate HHV-6 in several human cancers. In some instances, evidence suggests that HHV-6 may cooperate with other viruses, including EBV, HPV, and HHV-8, in the development of cancer, and HHV-6 may have a role in such conditions as nodular sclerosis Hodgkin lymphoma, gastrointestinal cancer, glial tumors, and oral cancers. However, further studies will be required to determine the exact contributions of HHV-6 to tumorigenesis.

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“…Although the efficiency of HHV-6 infection of ECs in vitro was low, inhibition of angiogenesis was observed in 100% of cells, suggesting that probably it was associated to the expression of a soluble factor, conditioning the angiogenic behavior of all cultured cells 5 . Recently, it was also shown that U94 inhibits tumor driven angiogenesis, decreasing tumor invasion and metastasis 10 .…”

Section: Introductionmentioning

confidence: 99%

Human Herpesvirus 6A and 6B inhibit in vitro angiogenesis by induction of Human Leukocyte Antigen G

Rizzo

D’Accolti

Bortolotti

et al. 2018

Sci Rep

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We have previously reported that human herpesvirus 6 (HHV-6) infection of endothelial cells (ECs) induces the loss of angiogenic properties, through the expression of HHV-6 U94, possibly associated to the release of a soluble mediator. It is also known that the soluble isoform of HLA-G exhibits an anti-angiogenic function, important in implantation, transplantation and neoplastic development. In this study, we analyzed the expression of HLA-G in HHV-6 infected ECs, showing that both HHV-6A and HHV-6B infection induce a potent up-modulation of HLA-G, including both membrane and soluble isoforms. Interestingly, HHV-6A and HHV-6B induced different isoforms of HLA-G. The virus-induced increase of HLA-G was likely due to the expression of the U94 viral gene, that by itself was able to reproduce the effect of whole virus. The effect of U94 was mediated by human transcription factor ATF3, that induced HLA-G activation by recognizing a consensus sequence on its promoter. Virus-induced inhibition of ECs angiogenic ability directly correlated to HLA-G expression and release, and the addition of anti-HLA-G antibody restored the angiogenic properties of HHV6-infected ECs. The induction of HLA-G expression in ECs might represent an important mediator of HHV-6 induced effects.

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U94 of human herpesvirus 6 down-modulates Src, promotes a partial mesenchymal-to-epithelial transition and inhibits tumor cell growth, invasion and metastasis

Cited by 12 publications

References 48 publications

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Human Herpesvirus 6 and Malignancy: A Review

Human Herpesvirus 6A and 6B inhibit in vitro angiogenesis by induction of Human Leukocyte Antigen G

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