| Autor: |
Dai L; Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China.; Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA., Qiao J; Department of Pediatrics, East Hospital, Tongji University School of Medicine, Shanghai, China., Nguyen D; William Carey University College of Osteopathic Medicine, Hattiesburg, MS, USA., Struckhoff AP; Department of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA., Doyle L; Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA., Bonstaff K; Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA., Del Valle L; Department of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA., Parsons C; Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA., Toole BP; Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA., Renne R; Department of Molecular Genetics Microbiology, University of Florida, Gainesville, FL, USA., Qin Z; Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China.; Departments of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA. |
| Abstrakt: |
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. |
