Kaposi sarcoma-associated herpesvirus (KSHV) induces a functional tumor-associated phenotype for oral fibroblasts

Abstract

The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found with KS lesions, and KSHV establishes latent infection within human primary fibroblasts in vitro, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. Secretion of pro-migratory factors and intratumoral invasion are characteristics of tumor-associated fibroblasts (TAF) found in the microenvironment of non-viral malignancies. In the present study, we show that latent KSHV infection of primary human fibroblasts isolated from the oral cavity enhances their secretion of KS-promoting cytokines and intrinsic invasiveness through VEGF-dependent mechanisms. Moreover, we find that KSHV induces these effects through Sp1- and Egr2-dependent transcriptional activation of the extracellular matrix metalloproteinase inducer (emmprin). These data implicate KSHV activation of emmprin in the induction of a “TAF-like” phenotype for oral fibroblasts in the KS microenvironment and support the potential utility of targeting TAFs and/or emmprin in the treatment of oral KS.

Fluctuation of Rac1 activity is associated with the phenotypic and transcriptional heterogeneity of glioma cells

“…Microarray analyses have revealed upregulation of Egr2 in metastatic squamous cell carcinomas (Kim et al, 2006;Liu et al, 2008). Furthermore, in fibroblasts infected with Kaposi sarcoma-associated herpesvirus, Egr2 induces MMPs and extracellular matrix metalloproteinase inducer (Emmprin) (Dai et al, 2012). These observations strongly support the proposal that Egr2 is a key regulator of glioma invasion.…”

Dangerous liaisons: molecular basis for a syndemic relationship between Kaposi’s sarcoma and P. falciparum malaria

“…Recent studies demonstrated compelling evidence that de novo KSHV infection of human endothelial cells as well as oral and fore-skin-derived fibroblasts results in upregulated expression of CD147 and that this effect is directly associated with various virological outcomes consistent with a pro-invasive, migratory, and pro-angiogenic phenotypes (Qin et al, 2010; Dai et al, 2012a,b). We have also found that KSHV upregulates CD147 not only in melanoma-derived cells but also in chronically infected lymphatic, microvascular, and brain endothelial cells (e.g., see Figure 4 ).…”

Lipids, lipid metabolism and Kaposi’s sarcoma-associated herpesvirus pathogenesis

“…In cell culture, KSHV is able to infect various types of human cells, such as B cells, endothelial cells, epithelial cells, and fibroblasts (Dai et al, 2012; Fontana et al, 2014; Kang and Myoung, 2017). Several membrane proteins including heparin sulfate proteoglycan (HSPG), DC-SIGN, integrin α3β1/αvβ3, EphA2 and xCT can act as cellular receptors for KSHV infection in a cell type-dependent manner (Birkmann et al, 2001; Akula et al, 2002; Kaleeba and Berger, 2006; Rappocciolo et al, 2006; Garrigues et al, 2008; Hahn et al, 2012).…”