KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin‐induced signal transduction

Abstract

The Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS)—one of the most common tumors arising in the setting of immune suppression. Hallmarks of KS lesions include KSHV-infected cells of endothelial lineage and neoangiogenesis. Pro-migratory factors secreted in the tumor microenvironment by KSHV-infected cells promote endothelial cell (EC) migration and angiogenesis, but existing approaches targeting these pathways are not widely utilized for KS. This underscores the need for additional characterization of KSHV-host interactions relevant to EC pathogenesis to identify new therapeutic targets. We recently demonstrated that de novo infection by KSHV promotes EC invasion through upregulation of emmprin—a multifunctional glycoprotein previously shown to induce tumor cell invasion and regional angiogenesis through upregulation of signal transduction and promotion of tumor-stroma interactions. The present study was undertaken to determine whether EC invasion for KSHV-infected cells is induced through activation of specific signal transduction pathways and pro-angiogenic factors by emmprin. We found that KSHV activation of emmprin induces PI3K/Akt- and mitogen-activated protein kinase (MAPK)-dependent secretion of vascular endothelial growth factor (VEGF). Moreover, EC invasion following de novo infection is induced by emmprin-dependent PI3K/Akt and MAPK activation of VEGF. These findings support the potential utility of targeting emmprin for reducing VEGF secretion and EC migration in the KS microenvironment.

Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients

“…4D-E ). We have previously shown that the mitogen-activated protein kinase (MAPK) pathway is involved in KSHV upregulation of CD147 [29]. Here we found that ectopic expression of LANA increased the phosphorylation of MAPK/ERK ( Fig.…”

Human Tumor Cells Induce Angiogenesis through Positive Feedback between CD147 and Insulin-Like Growth Factor-I

“…VEGF regulates the functions of ECs as confirmed by knockout of VEGF in vitro and in vivo [38], [39]. CD147 promoting angiogenic through HIF-1α, HIF-2α and VEGF pathways has already been reported in various tumors [16], [17], [18]. Recent study showed that CD147 regulated VEGF expression via the PI3K-Akt and MAPK (mitogen-activated protein kinase)-dependent signaling pathway [16], [40].…”

An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes

“…Cell invasion is a feature of KS and KSHV infection of human primary endothelial cells has been reported to promote cell migration and invasion [56,57]. Using a Matrigel-transwell assay, we investigated the invasive property of KSHV-infected PDLSCs.…”

“…KSHV-infected PDLSC showed increased migration and invasion activity (Fig 8A). In addition, PDLSCs in the KSHV-PDLSC conditioned medium also had elevated migration and invasion (Fig 8B), suggesting the KSHV-mediated cell migration is paracrine regulated, possibly through VEGF [57]. shRNA-mediated knock down of APE1 led to a significant decrease in cell invasion ability in both KSHV-infected PDLSCs and the use of the conditioned media (Fig 8C and 8D).…”