U94 of human herpesvirus 6 down-modulates Src, promotes a partial mesenchymal-to-epithelial transition and inhibits tumor cell growth, invasion and metastasis
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Francesca Caccuri1,*, Roberto Ronca1,*, Andrea S. Laimbacher2, Angiola Berenzi3, Nathalie Steimberg3, Federica Campilongo1, Pietro Mazzuca1, Arianna Giacomini1, Giovanna Mazzoleni3, Anna Benetti3, Elisabetta Caselli4, Marco Presta1, Dario Di Luca4, Cornel Fraefel2 and Arnaldo Caruso1
1Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
2Institute of Virology, University of Zurich, Zurich, Switzerland
3Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
4Department of Medical Sciences, University of Ferrara, Ferrara, Italy
*These authors have contributed equally to this work
Francesca Caccuri, email: firstname.lastname@example.org
Keywords: HHV-6 U94, HSV-1 amplicon vector, mesenchymal-to-epithelial transition, Src signaling pathway, cancer development and metastasis
Received: December 15, 2016 Accepted: April 21, 2017 Published: May 11, 2017
U94, the latency gene of human herpesvirus 6, was found to inhibit migration, invasion and proliferation of vascular endothelial cells (ECs). Because of its potent anti-migratory activity on ECs, we tested the capability of U94 to interfere with the individual steps of the metastatic cascade. We examined the U94 biological activity on the human breast cancer cell line MDA-MB 231, as a model of highly aggressive cancer cell. Here we show that the expression of U94 delivered by an HSV-1-based amplicon promoted down-modulation of Src and downstream molecules linked to cell motility and proliferation. Indeed, U94 expression strongly inhibited cell migration, invasiveness and clonogenicity. We investigated the effects of U94 in a three-dimensional rotary cell-culture system and observed the ability of U94 to modify tumor cell morphology by inducing a partial mesenchymal-to-epithelial transition. In fact, despite U94 did not induce any expression of the epithelial marker E-cadherin, it down-modulated different mesenchymal markers as β-catenin, Vimentin, TWIST, Snail1, and MMP2. In vivo data on the tumorigenicity of MDA-MB 231 displayed the capability of U94 to control tumor growth, invasiveness and metastasis, as well as tumor-driven angiogenesis. The antitumor U94 activity was also confirmed on the human cervical cancer cell line HeLa. The ability of U94 to inhibit cell growth, invasion and metastasis opens the way to a promising field of research aimed to develop new therapeutic approaches for treating tumor and cancer metastasis.
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