Stromelysin-3 is overexpressed by stromal elements in primary non-small cell lung cancers and regulated by retinoic acid in pulmonary fibroblasts.
Stromelysin-3 (STR-3) is a recently characterized matrix metalloproteinase (MMP) that was cloned on the basis of differential expression in benign and malignant breast tumors. This MMP has a unique processing mechanism and substrate specificity. Unlike previously characterized MMPs that are secreted as inactive zymogens, STR-3 is processed within the constitutive secretory pathway and secreted as an active enzyme. Although STR-3 has a characteristic MMP structure, the enzyme does not hydrolyze many of the extracellular matrix components that are substrates for other MMPs. However, STR-3 cleaves certain serine protease inhibitors (serpins), including the alpha 1 proteinase inhibitor (alpha 1 anti-trypsin). Because alpha 1 proteinase inhibitor deficiency has a known pathogenetic role in pulmonary disease, the role of STR-3 in non-small cell lung carcinomas (NSCLC) is of great interest. STR-3 transcripts and protein were significantly more abundant in primary NSCLC than in adjacent normal lung specimens in an extensive panel of stage I-III squamous cell and adenocarcinomas. The major form of STR-3 detectable in the primary NSCLC was the mature fully processed active enzyme. STR-3 transcripts and protein were primarily localized to NSCLC stromal elements, prompting analysis of STR-3 induction in normal pulmonary fibroblasts. Although STR-3 could be induced in normal pulmonary fibroblasts with growth factors (basic fibroblast growth factor and platelet-derived growth factor) and/or 12-O-tetradecanoylphorbol-13-acetate, STR-3 induction was inhibited by all-trans retinoic acid, a commonly used chemopreventive agent for aerodigestive tract malignancies. Taken together, these data suggest that STR-3 may be a novel marker and potential therapeutic target in NSCLC.
Anderson
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IC
Division of Hematologic Malignancies, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sugarbaker
D J
DJ
Ganju
R K
RK
Tsarwhas
D G
DG
Richards
W G
WG
Sunday
M
M
Kobzik
L
L
Shipp
M A
MA
D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000201:enzymology*; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D008970:Molecular Weight; D017154:Stromal Cells / Q000201:enzymology; D014212:Tretinoin / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D000515:alpha 1-Antitrypsin; D014212:Tretinoin; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases