Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential role in mediating adult T-cell leukemia invasiveness.
Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and of tropical spastic paraparesis/HTLV-I-associated myelopathy. Infiltration of various tissues by circulating leukemic cells is a characteristic of ATL. Matrix metalloproteinases (MMPs), which mediate the degradation of the basement membrane and extracellular matrix, play an important role in metastasis and tumor cell dissemination. The aim of this study was to explore whether expression of MMP-2 and MMP-9 was deregulated by HTLV-I infection. The data showed that HTLV-I-infected T-cell lines expressed high levels of MMP-9 compared with uninfected T-cell lines. In contrast, the levels of the related MMP-2 were not significantly altered by HTLV-I infection. In addition, the elevated expression of MMP-9 in HTLV-I-infected cells was attributable to the action of the viral transactivator protein Tax. The results show that Tax can activate the MMP-9 promoter and induce MMP-9 expression in T cells, indicating that the constitutive expression of MMP-9 in virus-infected cell lines is at least in part mediated by Tax. Activation of the MMP-9 promoter by Tax occurs mainly through the action of NF-kappaB and SP-1. The biologic significance of these observations was validated by the following 2 findings: MMP-9 expression was increased in primary ATL cells, and plasma MMP-9 levels were elevated in ATL patients. In addition, plasma levels of MMP-9 correlated with organ involvement in ATL patients. Together these data suggest that overexpression of MMP-9 in HTLV-I- infected cells may be in part responsible for the invasiveness of ATL cells.
Mori
Naoki
N
Departments of Preventive Medicine and AIDS Research, and Pathology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. n-mori@net.nagasaki-u.ac.jp
Sato
Hiroshi
H
Hayashibara
Toshihisa
T
Senba
Masachika
M
Hayashi
Tomayoshi
T
Yamada
Yasuaki
Y
Kamihira
Shimeru
S
Ikeda
Shuichi
S
Yamasaki
Yoshihiro
Y
Morikawa
Shigeru
S
Tomonaga
Masao
M
Geleziunas
Romas
R
Yamamoto
Naoki
N
D004790:Enzyme Induction / Q000187:drug effects; D016356:Gene Products, tax / Q000494:pharmacology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D017254:Leukemic Infiltration / Q000139:chemically induced* / Q000209:etiology; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011033:Podophyllin / Q000031:analogs & derivatives* / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D016356:Gene Products, tax; D016328:NF-kappa B; D012333:RNA, Messenger; C003170:mitopodozide; D011033:Podophyllin; D020780:Matrix Metalloproteinase 9; D011034:Podophyllotoxin