摘要：

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-3b 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. Citation: Zhou F, Xue M, Qin D, Zhu X, Wang C, et al. (2013) HIV-1 Tat Promotes Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) vIL-6-Induced Angiogenesis and Tumorigenesis by Regulating PI3K/PTEN/AKT/GSK-3b Signaling Pathway. PLoS ONE 8(1): e53145. doi:10.1371/journal.pone.0053145 Editor: Robert E. Means, Yale Medical School, United States of America Received September 1, 2012; Accepted November 23, 2012; Published January 2, 2013 Copyright: 2013 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Basic Research Program of China (973 Program) (2011CB504803), National Natural Science Foundation of China (grants 30972619 and 81171552 to C.L., 30900064 to D.Q., and 31270199 to Z.B.), Natural Science Foundation of Ministry of Education of Jiangsu Province (great project 10KJA310032 to C.L. and grant 09KJB310007 to D.Q.), Research Fund for the Doctoral Program of Higher Education of China (New Teacher Fund, grant 20093234120004 to D.Q.), Natural Science Foundation of Jiangsu Province (BK2010577 to N.F.), Jiangsu Province’s Outstanding Medical Academic Leader Program (RC201178 to N.F.), and China Postdoctoral Science Foundation (2012M511304 to Z.B.).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist * E-mail: clu@njmu.edu.cn . These authors contributed equally to this work.

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