Matrix Metalloproteinase-21 Is Expressed Epithelially During Development and in Cancer and Is Up-Regulated by Transforming Growth Factor-β1 in Keratinocytes

Abstract

SUMMARY: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-␤1 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, ␤-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. (Lab Invest 2003, 83:1887-1899.

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

“…Expression of mRNA for MMP15 and MMP20 in fetal and adult lungs shows no significant changes with developmental stage, whereas MMP2 and MMP14 decrease with age (229). MMP21 is expressed transiently during embryonic development with expression peaking around days 11-13.5 as detected by PCR and may be associated with neuronal cells (3,160). Amidst all the variation, two key MMPs stand out as being of major importance during development: MMP2 and MMP14 (MT1-MMP; is upregulated after birth (34).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Transcription factors binding sites suggest that its expression should be modulated during differentiative processes and in embryogenesis (Ahokas et al, 2002(Ahokas et al, , 2003Skoog et al, 2009). …”

Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma

“…17,21 Commercial TIMP-4 (Applied Biosystems: primer set Hs00162784_m1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Applied Biosystems, VIC-TAMRA, Art. No.…”

“…Diaminobenzidine (DAB) or 3-amino-9-ethylcarbazole (AEC) (cells cultured on chamber slides) was used as chromogenic substrate, and sections were counterstained with Mayer's hematoxylin. Samples were immunostained using polyclonal antibodies to MMP-26 (1:150), 21 MMP-21 (1:150), 17 TIMP-4 (1:700) (Neomarkers, RB-1542-P), and g-2 chain of laminin-5 (1:700, a gift from Professor Karl Tryggvason, Karolinska Institute, Sweden) 35 as well as by using monoclonal antibodies to MMP-7 (IM40L, 1:100, Calbiochem). MMP-21 and laminin-5 stainings required pre-treatment with 10 mg/ml trypsin, and MMP-7, -26, and TIMP-4 pre-treatment in þ 951C water bath for 30 min in DakoCytomation citratebuffer.…”

“…15 MMP-21, which our group cloned from human placenta cDNA, 16 has important functions during fetal development and in cancer biology. 17,18 MMP-21 is regulated at least in keratinocytes by transforming growth factor b-1 (TGFb1) and is present at the invasive front of cutaneous and esophageal SCCs in epithelial cancer cells 17,18 but not yet in dysplastic cells. MMP-21 can also be expressed by macrophages and fibroblasts in vivo and in vitro 19 and by neutrophils in vivo.…”