Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression.
Lung cancer is more deadly than colon, breast, and prostate cancers combined, and treatment improvements have failed to improve prognosis significantly. Here, we identify a critical mediator of lung cancer progression, Rac1b, a tumor-associated protein with cell-transforming properties that are linked to the matrix metalloproteinase (MMP)-induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. We show that expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development and that activation of EMT by MMP-induced expression of Rac1b gave rise to lung adenocarcinoma in the transgenic mice through bypassing oncogene-induced senescence. Rac1b is expressed abundantly in stages 1 and 2 of human lung adenocarcinomas and, hence, is an attractive molecular target for the development of new therapies that prevent progression to later-stage lung cancers.
Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA. stallingsmann.melody@mayo.edu
Melody L
ML
Stallings-Mann
Jens
J
Waldmann
Ying
Y
Zhang
Erin
E
Miller
Mona L
ML
Gauthier
Daniel W
DW
Visscher
Gregory P
GP
Downey
Evette S
ES
Radisky
Alan P
AP
Fields
Derek C
DC
Radisky
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000375:Aging / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D014746:Vimentin; D019278:Matrix Metalloproteinase 3; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein