Abstract
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is etiologically associated with KS, the most common AIDS-related malignancy. KS is characterized by vast angiogenesis and hyperproliferative spindle cells. We have previously reported that HIV-1 Tat can trigger KSHV reactivation and accelerate Kaposin A-induced tumorigenesis. Here, we explored Tat promotion of KSHV vIL-6-induced angiogenesis and tumorigenesis. Tat promotes vIL-6-induced cell proliferation, cellular transformation, vascular tube formation and VEGF production in culture. Tat enhances vIL-6-induced angiogenesis and tumorigenesis of fibroblasts and human endothelial cells in a chicken chorioallantoic membrane (CAM) model. In an allograft model, Tat promotes vIL-6-induced tumorigenesis and expression of CD31, CD34, SMA, VEGF, b-FGF, and cyclin D1. Mechanistic studies indicated Tat activates PI3K and AKT, and inactivates PTEN and GSK-3β in vIL-6 expressing cells. LY294002, a specific inhibitor of PI3K, effectively impaired Tat’s promotion of vIL-6-induced tumorigenesis. Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV-8), is a c2-herpesvirus
We examined the effect of Tat on the proliferation of vIL-6expressing cells using MTT assay. vIL-6-expressing cells 4E3 and 3D10 had higher proliferation rates compared to Mock cells (Fig. 1B)
Consistent with these results, soluble Tat accelerated the proliferation of vIL-6expressing fibroblasts and endothelial cells (Fig. 1D and 1E), while it was functional in chloramphenicol acetyltransferase (CAT) assay (Fig. S2A and S2B)
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV-8), is a c2-herpesvirus. KSHV is linked to the development of Kaposi’s sarcoma (KS) [1], primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [2]. KS is a vascular neoplasm of proliferative endothelial spindle cells. KS tumors contain abnormal and leaky vessels and extravasated red blood cells with haemosiderin deposits [3]. KSHV infection is necessary for the development of KS, it is not sufficient. The most important cofactor that contributes to KS development is HIV coinfection. The incidence of KS is 1 in 100,000 in the general population, but it is increased to 1 in 20 in HIV-infected individuals [4], and 1 in 3 in HIV-
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