Overexpression of Sprouty 2 in mouse lung epithelium inhibits urethane-induced tumorigenesis.
Members of the Sprouty family encode novel proteins that are thought to function primarily as intracellular antagonists of the Ras-signaling pathway. Increased Ras signaling is a critical characteristic of human lung adenocarcinoma, the most common type of non-small cell lung cancer. Sprouty 2 is expressed in the lung epithelium, the tissue layer from which lung cancers arise. We hypothesized that overexpression of Sprouty 2 in the distal lung epithelium would inhibit lung tumorigenesis. To test the hypothesis, the consequences of overexpressing Sprouty 2 in the distal lung epithelium on urethane-induced mouse lung tumorigenesis were determined. Urethane is a chemical carcinogen found in tobacco smoke that causes activating mutations in Kras and induces lung tumors in mice. Sprouty 2-overexpressor mice developed significantly fewer lung tumors compared with their littermate controls (13.2 +/- 1.1 versus 18.1 +/- 1.3, P = 0.006). Tumor diameter was also significantly smaller in Sprouty 2 overexpressors (0.85 mm +/- 0.03 versus 0.95 mm +/- 0.02, P = 0.005). Sprouty 2 overexpression did not alter Kras mutational frequencies in urethane-induced tumors, suggesting that the tumor-suppressing effect of Sprouty 2 overexpression acts at a stage after Kras mutation, perhaps by interfering with receptor tyrosine kinase-induced signaling. These results demonstrate that Sprouty 2 overexpression inhibited both tumor initiation and subsequent tumor growth.
Minowada
George
G
Division of Pulmonary and Critical Care Medicine, Case Western Reserve University, University Hospitals of Cleveland, Ohio, USA.
Miller
York E
YE
D048868:Adaptor Proteins, Signal Transducing; D000469:Alkaline Phosphatase; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D014520:Urethane / Q000633:toxicity*
D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D014520:Urethane; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)