Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis.
Expression of interleukin-8 (IL-8) by human melanoma cells correlates with their metastatic potential. Moreover, UV-B irradiation of primary cutaneous melanoma cells induces IL-8 mRNA and protein production and increases both tumor growth and metastasis in nude mice. Although IL-8 has been shown to be an angiogenic factor, the biological consequences of increased IL-8 production by melanoma cells and the role of IL-8 in the metastatic process remains unclear. The purpose of this study was to determine the role of IL-8 in tumor growth and metastasis of human melanoma cells. Nonmetastatic SB-2 melanoma cells with negligible levels of IL-8 were transfected with IL-8 cDNA and subsequently analyzed for changes in their tumorigenic and metastatic potential. Enforced expression of IL-8 rendered the melanoma cells highly tumorigenic and increased their metastatic potential as compared with parental and control transfected cells. The IL-8-transfected cells displayed up-regulation in M(r) 72,000 collagenase type IV (MMP-2) mRNA and collagenase activity and increased invasiveness through Matrigel-coated filters. Moreover, when the MMP-2 promoter was linked upstream of the chloramphenicol acetyltransferase (CAT) reporter gene, CAT activity was up-regulated in IL-8 but not in control transfected cells, suggesting that IL-8 is involved in MMP-2 gene transcription. Activation of type IV collagenase by IL-8 can enhance the invasion of host stroma by the tumor cells and increase angiogenesis and, hence, metastasis.
Luca
M
M
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Huang
S
S
Gershenwald
J E
JE
Singh
R K
RK
Reich
R
R
Bar-Eli
M
M
D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D020778:Matrix Metalloproteinase 2; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016209:Interleukin-8; D012333:RNA, Messenger; D015500:Chloramphenicol O-Acetyltransferase; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2