Matrix metalloproteinase-21 is expressed epithelially during development and in cancer and is up-regulated by transforming growth factor-beta1 in keratinocytes.
Human matrix metalloproteinase-21 (MMP-21), the newest member of the MMP gene family, has been suggested to play an important role in embryogenesis and tumor progression and to be a target of the Wnt, Pax, and Notch signaling pathways. Here we report detection of MMP-21 by RT-PCR in mouse embryos aged 10.5, 12.5, 13.5, and 16.5 days, as well as in various adult murine organs. In both humans and mice, MMP-21 protein was detected in the epithelial cells of developing kidney, intestine, neuroectoderm, and skin but not in normal adult skin using immunohistochemistry with two unrelated antibodies. However, it was present in invasive cancer cells of aggressive subtypes of basal and squamous cell carcinomas, although it was not expressed in skin disorders characterized by mere keratinocyte hyperproliferation. Of several cytokines tested, transforming growth factor-beta1 induced MMP-21 in vitro in HaCaTs and keratinocytes as judged by real-time quantitative TaqMan PCR. Although suprabasal differentiating keratinocytes expressed MMP-21 in developing skin in vivo, MMP-21-positive keratinocytes were detected by immunohistochemistry in both low and high calcium cultures. MMP-21 expression was not up-regulated by ras transformation in HaCaT cell lines (HaCaT, A5, II-4, and RT3); in skin and colon cancers, its expression did not associate with apoptosis, beta-catenin transactivation, or epithelial MMPs-9 and -10. However, MMP-21 protein was found in the same regions as MMP-7 but not in the same cells. Our results suggest that during development, MMP-21 expression is temporally and spatially tightly controlled. Unlike many classical MMPs, it is present in various normal adult tissues. Among epithelial MMPs, MMP-21 has a unique expression pattern in cancer.
Ahokas
Katja
K
Department of Dermatology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
Lohi
Jouko
J
Illman
Sara A
SA
Llano
Elena
E
Elomaa
Outi
O
Impola
Ulla
U
Karjalainen-Lindsberg
Marja-Liisa
ML
Saarialho-Kere
Ulpu
U
D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000196:embryology / Q000201:enzymology*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D053505:Matrix Metalloproteinases, Secreted; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C471969:MMP21 protein, human; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted