Regulation of the Mr 72,000 type IV collagenase by the type I insulin-like growth factor receptor.
The Mr 72,000 type IV collagenase [matrix metalloproteinase 2 (MMP-2)] is known to play a central role in the process of invasion and metastasis, but its regulation is not clearly understood. We investigated the role of the type I insulin-like growth factor (IGF-I) in the regulation of tumor cell invasion and the synthesis of MMP-2. Highly invasive murine Lewis lung carcinoma subline H-59 cells, in which expression of the IGF-I receptor (IGF-IR) was blocked by antisense mRNA, had a significantly reduced invasion in reconstituted basement membrane (Matrigel) as compared with that of controls. These cells had a decrease of up to 6-fold in the level of MMP-2 mRNA transcripts, as assessed by reverse transcription-PCR, and a corresponding reduction in protein synthesis, as assessed by the Western blot assay and gelatin zymography. Conversely, overexpression of IGF-IR in a second, poorly invasive carcinoma subline (M-27) with low endogenous levels of the receptor increased MMP-2 mRNA and protein expression by up to 7.5- and 4-fold, respectively. Ligand-mediated activation of the IGF-IR induced MMP-2 synthesis in both cell types. The results identify IGF-I as a regulator of MMP-2 expression and cellular invasion.
Department of Surgery, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.
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Navab
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Brodt
D016475:3T3 Cells / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure*; D018093:Gelatinases / Q000096:biosynthesis*; D018014:Gene Transfer Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2