Abstract
Sprouty negatively regulates receptor tyrosine kinase signals by inhibiting Ras/extracellular signal-regulated kinase (ERK) pathways. Sprouty is downregulated in breast, prostate and liver cancers and appears to function as a tumor suppressor. The role of sprouty in colonic neoplasia, however, has not been investigated. Sprouty-2 protein and mRNA transcripts were significantly upregulated in human colonic adenocarcinomas. Strikingly, the c-Met receptor was also upregulated in tumors with increased sprouty-2. To delineate a potential causal relationship between sprouty-2 and c-Met, K-ras mutant HCT-116 colon cancer cells were transduced with purified TAT-sprouty-2 protein or stably transfected with full-length human sprouty-2 gene. Sprouty-2 upregulation significantly increased cell proliferation by accelerating cell cycle transition. Sprouty-2 transfectants showed strong upregulation of c-Met protein and mRNA transcripts and hepatocyte growth factor-stimulated ERK and Akt phosphorylation and enhanced cell migration and invasion. In contrast, knockdown of c-Met by small interfering RNA (siRNA) significantly decreased cell proliferation, migration and invasion in sprouty-2 transfectants. Further, knockdown of sprouty-2 by siRNA in parental HT-29 and LS-174T colon cancer cells also decreased cell invasion. Sprouty-2 transfectants formed significantly larger tumor xenografts and showed increased proliferation and angiogenesis and suppressed apoptosis. Sprouty-2 tumors metastasized to the liver from cecal orthotopic implants, suggesting that sprouty-2 might also enhance metastatic signals. Thus, in colon cancer sprouty functions as an oncogene and its effects are mediated in part by c-Met upregulation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bloethner S, Chen B, Hemminki K, Muller-Berghaus J, Ugurel S, Schadendorf D et al. (2005). Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis 26: 1224–1232.
Brett D, Kemmner W, Koch G, Roefzaad C, Gross S, Schlag PM . (2001). A rapid bioinformatic method identifies novel genes with direct clinical relevance to colon cancer. Oncogene 20: 4581–4585.
Cabrita MA, Christofori G . (2008). Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11: 53–62.
Cerda SR, Bissonnette M, Scaglione-Sewell B, Lyons MR, Khare S, Mustafi R et al. (2001). PKC-delta inhibits anchorage-dependent and -independent growth, enhances differentiation, and increases apoptosis in CaCo-2 cells. Gastroenterology 120: 1700–1712.
Corps AN, Sowter HM, Smith SK . (1997). Hepatocyte growth factor stimulates motility, chemotaxis and mitogenesis in ovarian carcinoma cells expressing high levels of c-met. Int J Cancer 73: 151–155.
Dougherty U, Cerasi D, Taylor I, Kocherginsky M, Tekin U, Badal S et al. (2009). Epidermal growth factor receptor is required for colonic tumor promotion by dietary fat in the azoxymethane/dextran sulfate sodium. Clin Cancer Res 15: 6780–6789.
Edwin F, Singh R, Endersby R, Baker SJ, Patel TB . (2006). The tumor suppressor PTEN is necessary for human Sprouty 2-mediated inhibition of cell proliferation. J Biol Chem 281: 4816–4822.
Egan JE, Hall AB, Yatsula BA, Bar-Sagi D . (2002). The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci USA 99: 6041–6046.
Fang X, Yu S, Eder A, Mao M, Bast Jr RC, Boyd D et al. (1999). Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18: 6635–6640.
Fong CW, Chua MS, McKie AB, Ling SH, Mason V, Li R et al. (2006). Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma. Cancer Res 66: 2048–2058.
Fong CW, Leong HF, Wong ES, Lim J, Yusoff P, Guy GR . (2003). Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. J Biol Chem 278: 33456–33464.
Fujita S, Sugano K . (1997). Expression of c-met proto-oncogene in primary colorectal cancer and liver metastases. Jpn J Clin Oncol 27: 378–383.
Gross I, Bassit B, Benezra M, Licht JD . (2001). Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem 276: 46460–46468.
Guy GR, Wong ES, Yusoff P, Chandramouli S, Lo TL, Lim J et al. (2003). Sprouty: how does the branch manager work? J Cell Sci 116: 3061–3068.
Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA . (1998). Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92: 253–263.
Hall AB, Jura N, DaSilva J, Jang YJ, Gong D, Bar-Sagi D . (2003). hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Curr Biol 13: 308–314.
Hanafusa H, Torii S, Yasunaga T, Nishida E . (2002). Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4: 850–858.
Harris RE . (2009). Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17: 55–67.
Huerta S, Goulet EJ, Livingston EH . (2006). Colon cancer and apoptosis. Am J Surg 191: 517–526.
Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G . (2001). Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 152: 1087–1098.
Kammula US, Kuntz EJ, Francone TD, Zeng Z, Shia J, Landmann RG et al. (2007). Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett 248: 219–228.
Kanayama M, Takahara T, Yata Y, Xue F, Shinno E, Nonome K et al. (2007). Hepatocyte growth factor promotes colonic epithelial regeneration via Akt signaling. Am J Physiol Gastrointest Liver Physiol 293: G230–G239.
Kermorgant S, Aparicio T, Dessirier V, Lewin MJ, Lehy T . (2001). Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. Carcinogenesis 22: 1035–1042.
Khare S, Cerda S, Wali RK, von Lintig FC, Tretiakova M, Joseph L et al. (2003). Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer. Cancer Res 63: 3517–3523.
Khare S, Mustafi R, Cerda S, Yuan W, Jagadeeswaran S, Dougherty U et al. (2008). Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein. Nutr Cancer 60: 389–400.
Kim HJ, Bar-Sagi D . (2004). Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 5: 441–450.
Kwabi-Addo B, Wang J, Erdem H, Vaid A, Castro P, Ayala G et al. (2004). The expression of Sprouty1, an inhibitor of fibroblast growth factor signal transduction, is decreased in human prostate cancer. Cancer Res 64: 4728–4735.
Lee CC, Putnam AJ, Miranti CK, Gustafson M, Wang LM, Vande Woude GF et al. (2004). Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis. Oncogene 23: 5193–5202.
Lee M . (2006). Raf-1 kinase activation is uncoupled from downstream MEK/ERK pathway in cells treated with Src tyrosine kinase inhibitor PP2. Biochem Biophys Res Commun 350: 450–456.
Li N, Lorinczi M, Ireton K, Elferink LA . (2007). Specific Grb2-mediated interactions regulate clathrin-dependent endocytosis of the cMet-tyrosine kinase. J Biol Chem 282: 16764–16775.
Lim J, Yusoff P, Wong ES, Chandramouli S, Lao DH, Fong CW et al. (2002). The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes. Mol Cell Biol 22: 7953–7966.
Lito P, Mets BD, Kleff S, O'Reilly S, Maher VM, McCormick JJ . (2008). Evidence that sprouty 2 is necessary for sarcoma formation by H-Ras oncogene-transformed human fibroblasts. J Biol Chem 283: 2002–2009.
Lo TL, Fong CW, Yusoff P, McKie AB, Chua MS, Leung HY et al. (2006). Sprouty and cancer: the first terms report. Cancer Lett 242: 141–150.
Lo TL, Yusoff P, Fong CW, Guo K, McCaw BJ, Phillips WA et al. (2004). 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 64: 6127–6136.
McKie AB, Douglas DA, Olijslagers S, Graham J, Omar MM, Heer R et al. (2005). Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer. Oncogene 24: 2166–2174.
Minowada G, Miller YE . (2009). Overexpression of Sprouty 2 in mouse lung epithelium inhibits urethane-induced tumorigenesis. Am J Respir Cell Mol Biol 40: 31–37.
Nakanishi K, Fujimoto J, Ueki T, Kishimoto K, Hashimoto-Tamaoki T, Furuyama J et al. (1999). Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via phosphatidylinositol 3-kinase. Clin Exp Metastasis 17: 507–514.
Nigg EA . (1995). Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays 17: 471–480.
Pelletier G, Roulot D, Davion T, Masliah C, Causse X, Oberti F et al. (2003). A randomized controlled trial of ursodeoxycholic acid in patients with alcohol-induced cirrhosis and jaundice. Hepatology 37: 887–892.
Poppleton HM, Edwin F, Jaggar L, Ray R, Johnson LR, Patel TB . (2004). Sprouty regulates cell migration by inhibiting the activation of Rac1 GTPase. Biochem Biophys Res Commun 323: 98–103.
Rozen S, Skaletsky H . (2000). Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132: 365–386.
Rubin C, Litvak V, Medvedovsky H, Zwang Y, Lev S, Yarden Y . (2003). Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops. Curr Biol 13: 297–307.
Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M et al. (2003). Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nat Cell Biol 5: 427–432.
Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M et al. (1999). Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18: 2343–2350.
Shoji T, Konno H, Tanaka T, Sakaguchi T, Sunayama K, Baba M et al. (2003). Orthotopic implantation of a colon cancer xenograft induces high expression of cyclooxygenase-2. Cancer Lett 195: 235–241.
Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T et al. (2002). Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 99: 4465–4470.
Sutterluty H, Mayer CE, Setinek U, Attems J, Ovtcharov S, Mikula M et al. (2007). Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms. Mol Cancer Res 5: 509–520.
Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M et al. (2003). c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9: 1480–1488.
Teranishi N, Naito Z, Ishiwata T, Tanaka N, Furukawa K, Seya T et al. (2007). Identification of neovasculature using nestin in colorectal cancer. Int J Oncol 30: 593–603.
Trusolino L, Comoglio PM . (2002). Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2: 289–300.
Vaculova A, Hofmanova J, Soucek K, Kozubik A . (2006). Different modulation of TRAIL-induced apoptosis by inhibition of pro-survival pathways in TRAIL-sensitive and TRAIL-resistant colon cancer cells. FEBS Lett 580: 6565–6569.
Wang L, Chen W, Xie X, He Y, Bai X . (2008). Celecoxib inhibits tumor growth and angiogenesis in an orthotopic implantation tumor model of human colon cancer. Exp Oncol 30: 42–51.
Wong ES, Lim J, Low BC, Chen Q, Guy GR . (2001). Evidence for direct interaction between Sprouty and Cbl. J Biol Chem 276: 5866–5875.
Yigzaw Y, Cartin L, Pierre S, Scholich K, Patel TB . (2001). The C terminus of sprouty is important for modulation of cellular migration and proliferation. J Biol Chem 276: 22742–22747.
Yuan JS, Reed A, Chen F, Stewart Jr CN . (2006). Statistical analysis of real-time PCR data. BMC Bioinform 7: 85.
Zeng Z, Weiser MR, D'Alessio M, Grace A, Shia J, Paty PB . (2004). Immunoblot analysis of c-Met expression in human colorectal cancer: overexpression is associated with advanced stage cancer. Clin Exp Metast 21: 409–417.
Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A et al. (2008). c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett 265: 258–269.
Acknowledgements
These studies were funded in part by Grant CA036745 (to M Bissonnette) and VA merit award (to S Khare).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Holgren, C., Dougherty, U., Edwin, F. et al. Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas. Oncogene 29, 5241–5253 (2010). https://doi.org/10.1038/onc.2010.264
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.264
Keywords
This article is cited by
-
Increased SPRY1 expression activates NF-κB signaling and promotes pancreatic cancer progression by recruiting neutrophils and macrophages through CXCL12-CXCR4 axis
Cellular Oncology (2023)
-
PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability
Oncogenesis (2023)
-
Integrative Bioinformatics approaches to therapeutic gene target selection in various cancers for Nitroglycerin
Scientific Reports (2021)
-
Loss of Spry1 reduces growth of BRAFV600-mutant cutaneous melanoma and improves response to targeted therapy
Cell Death & Disease (2020)
-
SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma
Cell Death & Disease (2018)