Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model.
Lung cancer is one of the leading cancer malignancies, with a five-year survival rate of only ~15%. We have developed a lentiviral-vector-mediated mouse model, which enables generation of non-small-cell lung cancer from less than 100 alveolar epithelial cells, and investigated the role of IKK2 and NF-κB in lung-cancer development. IKK2 depletion in tumour cells significantly attenuated tumour proliferation and significantly prolonged mouse survival. We identified Timp1, one of the NF-κB target genes, as a key mediator for tumour growth. Activation of the Erk signalling pathway and cell proliferation requires Timp-1 and its receptor CD63. Knockdown of either Ikbkb or Timp1 by short hairpin RNAs reduced tumour growth in both xenograft and lentiviral models. Our results thus suggest the possible application of IKK2 and Timp-1 inhibitors in treating lung cancer.
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Yifeng
Y
Xia
Narayana
N
Yeddula
Mathias
M
Leblanc
Eugene
E
Ke
Yonghui
Y
Zhang
Eric
E
Oldfield
Reuben J
RJ
Shaw
Inder M
IM
Verma
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics
D001549:Benzamides; C554587:Cd63 protein, mouse; D060149:Tetraspanin 30; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C506614:mirdametinib; D004159:Diphenylamine; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)