CD147 and downstream ADAMTSs promote the tumorigenicity of Kaposi's sarcoma-associated herpesvirus infected endothelial cells.

Lu Dai,Bryan P Toole,Zhiqiang Qin,Jimena Trillo-Tinoco,Chris Parsons,Augusto C Ochoa,Luis Del Valle,Yihan Chen,Jovanny Zabaleta,Karlie Bonstaff

doi:10.18632/oncotarget.6584

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS), which preferentially arise in immunocompromised patients and lack effective therapeutic options. We have previously shown that KSHV or viral protein LANA up-regulates the glycoprotein CD147, thereby inducing primary endothelial cell invasiveness. In the current study, we identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among downstream genes, two specific metalloproteases, ADAMTS1 and 9, are strongly expressed in AIDS-KS tissues and contribute to KSHV-infected endothelial cell invasiveness through up-regulation of IL-6 and VEGF. By using a KS-like nude mouse model, we found that targeting CD147 and downstream ADAMTSs significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, targeting CD147 and associated proteins may represent a promising therapeutic strategy against these KSHV-related malignancies.

Highlights

Kaposi sarcoma-associated herpesvirus (KSHV) represents one of major causative agent of cancers arising in immunocompromised patients, including Kaposi’s Sarcoma (KS) [1]
We first used the HumanHT-12 v4 Expression BeadChip (Illumina), which contains more than 47,000 probes derived from the NCBI RefSeq Release 38 and other sources, to study the gene profile altered within CD147-overexpressed Human umbilical vein endothelial cells (HUVEC) cells by using a recombinant adenoviral vector AdV-CD147 [11] or within KSHV-infected HUVEC cells
We found that 184 genes were significantly up-regulated and 148 were down-regulated (≥ 2 fold and p < 0.05) within CD147overexpressed endothelial cells; in KSHV-infected cells, 963 genes were up-regulated and 1042 down-regulated

Summary

Introduction

Kaposi sarcoma-associated herpesvirus (KSHV) represents one of major causative agent of cancers arising in immunocompromised patients, including Kaposi’s Sarcoma (KS) [1]. Despite the reduced incidence of KS in the era of combined Antiretroviral Therapy (cART) for Human Immunodeficiency Virus (HIV) infection, KS still remains the most common Acquired Immunodeficiency Syndrome (AIDS)associated tumor and a leading cause of morbidity and mortality in this setting [2, 3]. Transplant recipients who develop primary KSHV infection after transplantation have a relatively high probability of developing KSHV-related malignancies, especially KS [5], which is likely associated with the intensity of immunosuppressive treatment post-transplantation [6]. KSHV-induced malignancies, in particular KS, still represent a serious threat to immunosuppressed patients due to the lack of effective therapies. Many key questions regarding its mechanisms of oncogenesis still remain unanswered, hindering identification of rational targets and development of novel therapeutic strategies

Methods

Results

Conclusion