Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:10459-10471. https://doi.org/10.18632/oncotarget.7227

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Abstract

Lu Dai1,3,*, Jing Qiao4,*, David Nguyen5, Amanda P. Struckhoff6, Lisa Doyle3, Karlie Bonstaff3, Luis Del Valle6, Chris Parsons3, Bryan P. Toole7, Rolf Renne8 and Zhiqiang Qin1,2

1 Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China

2 Departments of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA

3 Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA

4 Department of Pediatrics, East Hospital, Tongji University School of Medicine, Shanghai, China

5 William Carey University College of Osteopathic Medicine, Hattiesburg, MS, USA

6 Department of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA

7 Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA

8 Department of Molecular Genetics Microbiology, University of Florida, Gainesville, FL, USA

* These authors have contributed equally to this work

Correspondence to:

Zhiqiang Qin, email:

Keywords: KSHV, Kaposi’s sarcoma, HO-1, SnPP

Received: December 20, 2015 Accepted: January 27, 2016 Published: February 07, 2016

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.


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