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

Oncotarget. 2016 Mar 1;7(9):10459-71. doi: 10.18632/oncotarget.7227.


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.

Keywords: HO-1; KSHV; Kaposi’s sarcoma; SnPP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Viral / metabolism
  • Apoptosis
  • Basigin / metabolism*
  • Carcinogenesis / drug effects
  • Cell Proliferation
  • DNA Damage / drug effects
  • HIV Infections / immunology
  • HIV Infections / virology
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Herpesvirus 8, Human / metabolism*
  • Human Umbilical Vein Endothelial Cells / pathology*
  • Human Umbilical Vein Endothelial Cells / virology
  • Humans
  • Metalloporphyrins / pharmacology
  • Mice
  • Mice, Nude
  • Necrosis / chemically induced
  • Nuclear Proteins / metabolism
  • Protoporphyrins / pharmacology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Sarcoma, Kaposi / pathology*
  • Sarcoma, Kaposi / virology


  • Antigens, Viral
  • Bsg protein, mouse
  • Metalloporphyrins
  • Nuclear Proteins
  • Protoporphyrins
  • RNA, Small Interfering
  • latency-associated nuclear antigen
  • Basigin
  • tin protoporphyrin IX
  • Heme Oxygenase-1