KSHV downregulation of galectin-3 in Kaposi's sarcoma.
Galectins are a family of proteins that share an affinity for beta-galactoside containing glycoconjugates. In prostate, ovarian and breast cancer, downregulation of galectin-3 is associated with malignancy and tumor progression. Kaposi's sarcoma (KS) is characterized as an angioproliferative tumor of vascular endothelial cells and produces rare B cell lymphoproliferative diseases in the form of primary effusion lymphomas and some forms of multicentric Castleman's disease. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of KS. We found reduced levels of galectin-3 expression in a significant fraction of latency-associated nuclear antigen (LANA)-positive spindle cell regions in human archival KS tissue and as measured in KS tissue microarrays. Here we demonstrate that galectin-3 protein expression is downregulated 10-fold in 10-day KSHV-infected dermal microvascular endothelial cells (DMVEC) accompanied by downregulation of message. There is loss of galectin-3 staining in KSHV-infected DMVEC by dual labeled immunohistochemistry in LANA-positive spindle cells. We observed a consistent downregulation of galectin-3 by time-course transcriptional analysis. Of the galectins assayed, only galectin-1 was also downregulated in KSHV-infected DMVEC. We examined 86 KS tumors; 19 were LANA positive (22%) and 67 LANA negative (78%). All 86 tumors were found to be galectin-3 positive; 11 of 19 showed reduced expression of galectin-3 in LANA-positive spindle cell regions. Our data suggest that KSHV vFLIP and LANA are the viral genes targeting galectin-3 downregulation. The contribution of host factors to the pathogenesis of KS is essential for early detection and development of innovative therapies for treatment.
Alcendor
Donald J
DJ
Meharry Medical College, School of Medicine, Comprehensive Center for AIDS Health Disparities Research and the Department of Microbial Pathogenesis and Immune Response, Hubbard Hospital 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN 37208-3599, USA. dalcendor@mmc.edu
Knobel
Susan M
SM
Desai
Prashant
P
Zhu
Wen Q
WQ
Vigil
Hollie E
HE
Hayward
Gary S
GS
D000956:Antigens, Viral / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D037502:Galectin 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008833:Microcirculation; D009687:Nuclear Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000821:virology*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D000956:Antigens, Viral; D037502:Galectin 3; D009687:Nuclear Proteins; C109540:latency-associated nuclear antigen