Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus

Lu Dai,Lisa Doyle,Amanda P Struckhoff,Zhiqiang Qin,Rolf Renne,Jing Qiao,Karlie Bonstaff,David Nguyen,Luis Del Valle,Bryan P Toole,Chris Parsons

doi:10.18632/oncotarget.7227

Abstract

Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation and lack effective therapeutic options. Heme oxygenase-1 (HO-1) has been reported as an important regulator of endothelial cell cycle control, proliferation and angiogenesis. HO-1 has also been found to be highly expressed in KSHV-infected endothelial cells and oral AIDS-KS lesions. We previously demonstrate that the multifunctional glycoprotein CD147 is required for KSHV/LANA-induced endothelial cell invasiveness. During the identification of CD147 controlled downstream genes by microarray analysis, we found that the expression of HO-1 is significantly elevated in both CD147-overexpressing and KSHV-infected HUVEC cells when compared to control cells. In the current study, we further identify the regulation of HO-1 expression and mediated cellular functions by both CD147 and KSHV-encoded LANA proteins. Targeting HO-1 by either RNAi or the chemical inhibitor, SnPP, effectively induces cell death of KSHV-infected endothelial cells (the major cellular components of KS) through DNA damage and necrosis process. By using a KS-like nude mouse model, we found that SnPP treatment significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, our data demonstrate the important role of HO-1 in the pathogenesis and tumorigenesis of KSHV-infected endothelial cells, the underlying regulatory mechanisms for HO-1 expression and targeting HO-1 may represent a promising therapeutic strategy against KSHV-related malignancies.

Highlights

Kaposi sarcoma-associated herpesvirus (KSHV) represents a principal causative agent of cancers arising in immunocompromised patients, such as Kaposi’s Sarcoma (KS) [1]
Our results indicated that the transcriptional level of Heme oxygenase-1 (HO-1) was increased ~25 and ~4.5 folds in CD147-overexpressing and KSHVinfected human umbilical vein endothelial cells (HUVEC), respectively (Figure 1A)
Our data demonstrate that Kaposi’s Sarcoma-associated Herpesvirus (KSHV) upregulates Heme oxygenases (HOs)-1 expression through CD147 in endothelial cells, and the high co-expression of these 2 proteins in Acquired Immunodeficiency Syndrome (AIDS)-KS tissues indicating their importance to tumor development

Summary

INTRODUCTION

Kaposi sarcoma-associated herpesvirus (KSHV) represents a principal causative agent of cancers arising in immunocompromised patients, such as Kaposi’s Sarcoma (KS) [1]. A recent study has shown the elevated HO-1 expression and activity in KSHV-infected endothelial cells as well as oral AIDS-KS lesions [13]. During KSHV de novo infection, only a small proportion of infected cells expressing vGPCR, since it is a lytic protein while most cells are in latency Another remaining question is that the mechanisms for KSHV activation of HO-1 through either viral proteins or host factors still remain largely unknown. In the current study we will continue to experimentally validate the regulation of HO-1 by CD147 and viral latent protein, investigate the role of HO-1 in KSHV-infected endothelial cell pathogenesis and tumorigenesis, and determine the anticancer effects of a HO-1 selective inhibitor by using an established KS-like xenograft model

RESULTS

DISCUSSION

MATERIALS AND METHODS