Matrilysin-1 mediates bronchiolization of alveoli, a potential premalignant change in lung cancer.
Matrilysin-1 (also called matrix metalloproteinase-7) is expressed in injured lung and in cancer but not in normal epithelia. Bronchiolization of the alveoli (BOA), a potential precursor of lung cancer, is a histologically distinct type of metaplasia that is composed of cells resembling airway epithelium in the alveolar compartment. We demonstrate that there is increased expression of matrilysin-1 in human lesions and BOA in the CC10-human achaete-scute homolog-1 transgenic mouse model. Forced expression of the matrilysin-1 gene in immortalized human normal airway epithelial BEAS-2B and HPLD1 cells, which do not normally express matrilysin-1, promoted cellular migration, suggesting a functional link for BOA formation via bronchiolar cell migration. In addition, matrilysin-1 stimulated proliferation and inhibited Fas-induced apoptosis, while a knockdown by RNA interference decreased cell growth, migration, and increased sensitivity to apoptosis. Western blotting demonstrated increased levels of phospho-p38 and phospho-Erk1/2 kinases after matrilysin-1 expression. Gene expression analysis uncovered several genes that were related to cell growth, migration/movement, and death, which could potentially facilitate bronchiolization. In vivo, the formation of BOA lesions was reduced when CC10-human achaete-scute homolog-1 mice were crossed with matrilysin-1 null mice and was correlated with reduced matrilysin-1 expression in BOA. We conclude that matrilysin-1 may play an important role in the bronchiolization of alveoli by promoting proliferation, migration, and attenuation of apoptosis involving multiple genes in the MAP kinase pathway.
Wang
Xiao-Yang
XY
Experimental Pathology Section, Cell and Cancer Biology Branch, CCR, NCI, NIH, 37 Convent Drive; Room.1056B, Bethesda, Maryland 20892, USA.
Demelash
Abeba
A
Kim
Heungnam
H
Jensen-Taubman
Sandra
S
Dakir
El Habib
el H
Ozbun
Laurent
L
Birrer
Michael J
MJ
Linnoila
R Ilona
RI
D000818:Animals; D055745:Bronchioles / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology*
C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7