Overexpression of Sprouty 2 in Mouse Lung Epithelium Inhibits Urethane-Induced Tumorigenesis
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SPRY2 negatively regulates Ras/MEK/ERK signaling and is a tumor suppressor in NSCLC in both mice and humans.
“SPRY2, in turn, negatively regulates Ras/MEK/ERK signaling and is a tumor suppressor in NSCLC in both mice (Minowada and Miller, 2004; Minowada and Miller, 2009; Shaw et al., 2007) and humans (Sutterluty et al., 2007).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Minowada and Miller, 2009
The study summary and Discussion (page unavailable) report fewer and smaller urethane-induced lung tumors in mice overexpressing Sprouty 2, supporting a tumor-suppressive effect in that mouse model. The Discussion says the findings are consistent with antagonism of Ras signaling, but the mechanism remains unclear; this paper does not demonstrate inhibition of MEK/ERK signaling. The citing sentence attributes the human NSCLC portion to a separate citation, not to this paper. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 32 · Cited by 22
Research works printed but not linked: 28
- [1]1. Zochbauer-Muller S, Gazdar AF, Minna JD. Molecular pathogenesis of lung cancer. Annu Rev Physiol 2002;64:681-708.
- [2]2. Sato M, Shames DS, Gazdar AF, Minna JD. A translational view of the molecular pathogenesis of lung cancer. J horac Oncol. 2007;2:327-343.
- [3]3. Khosravi-Far R, Der CJ. The Ras signal transduction pathway. Cancer Metastasis Rev 1994;13:67-89.
- [4]4. Malkinson AM. Primary lung tumors in mice as an aid for understanding, preventing, and treating human adenocarcinoma of the lung. Lung Cancer 2001;32:265-279.
- [5]5. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111-1116.
- [6]6. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A, Varmus HE. Induction and apoptotic regression of lung adenocarcinomas by regulation of a KRas transgene in the presence and absence of tumor suppressor genes. Genes Dev 2001;15:3249-3262.
- [7]7. Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA. sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 1998;92:253-263.
- [9]9. Minowada G, Jarvis LA, Chi CL, Neubuser A, Sun X, Hacohen N, Krasnow MA, Martin GR. Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 1999;126:4465-4475.
- [10]10. Cabrita MA, Christofori G. Sprouty proteins: antagonists of endothelial cell signaling and more. Thromb Haemost 2003;90:586-590.
- [11]11. Lee CC, Putnam AJ, Miranti CK, Gustafson M, Wang LM, Vande Woude GF, Gao CF. Overexpression of sprouty 2 inhibits HGF/SFmediated cell growth, invasion, migration, and cytokinesis. Oncogene 2004;23:5193-5202.
- [12]12. Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 2004;5:441-450.
- [13]13. Guy GR, Wong ES, Yusoff P, Chandramouli S, Lo TL, Lim J, Fong CW. Sprouty: how does the branch manager work? J Cell Sci 2003;116: 3061-3068.
- [14]14. Christofori G. Split personalities: the agonistic antagonist Sprouty. Nat Cell Biol 2003;5:377-379.
- [15]15. Mailleux AA, Tefft D, Ndiaye D, Itoh N, Thiery JP, Warburton D, Bellusci S. Evidence that SPROUTY2 functions as an inhibitor of mouse embryonic lung growth and morphogenesis. Mech Dev 2001;102:81-94.
- [16]16. Sutterluty H, Mayer CE, Setinek U, Attems J, Ovtcharov S, Mikula M, MikulitsW,MickscheM,BergerW.Down-regulationofSprouty2innonsmall cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms. Mol Cancer Res 2007;5:509-520.
- [18]18. Lobe CG, Koop KE, Kreppner W, Lomeli H, Gertsenstein M, Nagy A. Z/AP, a double reporter for cre-mediated recombination. Dev Biol 1999;208:281-292.
- [19]19. Perl AK, Tichelaar JW, Whitsett JA. Conditional gene expression in the respiratory epithelium of the mouse. Transgenic Res 2002;11: 21-29.
- [20]20. Tichelaar JW, Lu W, Whitsett JA. Conditional expression of fibroblast growth factor-7 in the developing and mature lung. J Biol Chem 2000; 275:11858-11864.
- [21]21. Nuzum EO, Malkinson AM, Beer DG. Specific Ki-ras codon 61 mutations may determine the development of urethan-induced mouse lung adenomas or adenocarcinomas. Mol Carcinog 1990;3:287-295.
- [22]22. Shimkin MB, Polissar MJ. Some quantitative observations on the induction and growth of primary pulmonary tumors in strain A mice receiving urethan. J Natl Cancer Inst 1955;16:75-97.
- [23]23. Dyson P, Heppleston AG. Cell kinetics of urethane induced murine pulmonary adenomata: I. The growth rate. BrJ Cancer 1975;31:405-416.
- [24]24. Lamerton LF, Steel GG. Cell population kinetics in normal and malignant tissues. Prog Biophys Mol Biol 1968;18:245-283.
- [25]25. Gunning WT, Kramer PM, Lubet RA, Steele VE, Pereira MA. Chemoprevention of vinyl carbamate-induced lung tumors in strain A mice. Exp Lung Res 2000;26:757-772.
- [26]26. Gunning WT, Kramer PM, Steele VE, Pereira MA. Chemoprevention by lipoxygenase and leukotriene pathway inhibitors of vinyl carbamateinduced lung tumors in mice. Cancer Res 2002;62:4199-4201.
- [27]27. Moody TW, Leyton J, Zakowicz H, Hida T, Kang Y, Jakowlew S, You L, Ozbun L, Zia H, Youngberg J, et al. Indomethacin reduces lung adenoma number in A/J mice. Anticancer Res 2001;21:1749-1755.
- [28]28. Jalbert G, Castonguay A. Effects of NSAIDs on NNK-induced pulmonary and gastric tumorigenesis in A/J mice. Cancer Lett 1992;66:21-28.
- [29]29. Kwabi-Addo B, Wang J, Erdem H, Vaid A, Castro P, Ayala G, Ittmann M. The expression of Sprouty1, an inhibitor of fibroblast growth factor signal transduction, is decreased in human prostate cancer. Cancer Res 2004;64:4728-4735.
- [30]30. Lo TL, Yusoff P, Fong CW, Guo K, McCaw BJ, Phillips WA, Yang H, Wong ES, Leong HF, Zeng Q, et al. The ras/mitogen-activated protein kinase pathway inhibitor and likely tumor suppressor proteins, sprouty 1 and sprouty 2 are deregulated in breast cancer. Cancer Res 2004;64:6127-6136.
- Authors
- Minowada, G., & Miller, Y. E.
- Affiliations
- University Hospitals of Cleveland (US)
- University of Colorado Health (US)
- Corresponding author
- Miller, York E.
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-01-01
- Volume
- 40
- Issue
- 1
- Pages
- 31-37
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- PMC
- PMC2720112
- OpenAlex
- W2023313811
- Cited by
- 22
- References
- 32
- Citations by year
- 2026: 1 · 2016: 1 · 2015: 5 · 2014: 2 · 2013: 1 · 2012: 1
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- U.S. Department of Veterans Affairs
- Case Western Reserve University
- University of California, San Francisco
- National Cancer Institute (P50-CA 58187, CA58187, IRG-91-022-09, P50CA058187)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Sprouty2, lung carcinogenesis, urethane-induced lung cancer, lung epithelium, Ras signaling, KRAS mutation, tumor suppression, non-small cell lung cancer, tumor growth inhibition, receptor tyrosine kinase signaling
- MeSH terms
- Alkaline Phosphatase, Animals, Carcinogens, Female, Humans, Isoenzymes, Lung Neoplasms, Male, Membrane Proteins, Mice, Transgenic, Urethane, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Respiratory Mucosa, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, GPI-Linked Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
