Direct activation of emmprin and associated pathogenesis by an oncogenic herpesvirus.
Emmprin (extracellular matrix metalloproteinase inducer) is a multifunctional glycoprotein expressed by cancer cells and stromal cells in the tumor microenvironment. Through both direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin induces tumor cell invasiveness and regional angiogenesis. The Kaposi's sarcoma-associated herpesvirus (KSHV) is a common etiology for cancers arising in the setting of immune suppression, including Kaposi's sarcoma and primary effusion lymphoma. However, whether emmprin expression and function are regulated by KSHV or other oncogenic viruses in the tumor microenvironment to promote viral cancer pathogenesis remains unknown. Fibroblasts and endothelial cells support latent KSHV infection and represent cellular components of Kaposi's sarcoma lesions. Therefore, we used primary human fibroblasts and endothelial cells to determine whether KSHV itself regulates emmprin expression, and whether KSHV-emmprin interactions mediate cell invasiveness. We found that KSHV promotes fibroblast and endothelial cell invasiveness following de novo infection through the upregulation of emmprin, and that this effect is mediated by the KSHV-encoded latency-associated nuclear antigen. We also found that emmprin promotes invasiveness, as well as colony formation, by primary effusion lymphoma cells derived from human tumors. Collectively, these data implicate KSHV activation of emmprin as an important mechanism for cancer progression and support the potential utility of targeting emmprin as a novel therapeutic approach for KSHV-associated tumors.
Qin
Zhiqiang
Z
Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Dai
Lu
L
Slomiany
Mark G
MG
Toole
Bryan P
BP
Parsons
Chris
C
D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D051926:Basigin / Q000378:metabolism*; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003588:Cytopathogenic Effect, Viral; D004730:Endothelium, Vascular / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D005455:Fluorescent Antibody Technique; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000378:metabolism / Q000821:virology*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D017735:Virus Latency
D000956:Antigens, Viral; D009687:Nuclear Proteins; D012333:RNA, Messenger; C109540:latency-associated nuclear antigen; D051926:Basigin
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