The aims of the current study were to evaluate whether recepteur d'origine nantais (RON) affects tumor cell behavior and oncogenic signaling pathways in colorectal cancer, and to examine the relationship of its expression with various clinicopathological parameters and patient survival.
Methods
Immunohistochemistry, Western blot and RT-PCR were used to detect the expression of the RON gene in human colorectal cancer tissue. To study the biological role of RON in tumor cell behavior and cellular signaling pathways, we used small interfering RNA (siRNA) to knock down RON gene expression in human colorectal cancer cell lines.
Results
Knockdown of RON inhibited the induction of the invasive growth phenotype and the activation of oncogenic signaling pathways including Akt, MAPK and β-catenin. RON overexpression was associated with tumor size, lymphovascular invasion, depth of invasion, lymph node metastasis, distant metastasis, tumor stage and poor survival.
Conclusions
These results suggest that RON overexpression may help in predicting poor clinical outcomes in colorectal cancer.
LabiancaR., MerelliB.: Screening and diagnosis for colorectal cancer: present and future.Tumori, 96: 889–901, 2010.
2.
AllanA.L., VantyghemS.A., TuckA.B., ChambersA.F.: Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis.Breast Dis, 26: 87–98, 2006.
ChambersA.F., GroomA.C., MacDonaldI.C.: Dissemination and growth of cancer cells in metastatic sites.Nat Rev Cancer, 2: 563–572, 2002.
5.
LuY., YaoH.P., WangM.H.: Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets.Cancer Lett, 257: 157–164, 2007.
6.
LeonisM.A., ThobeM.N., WaltzS.E.: Ron-receptor tyrosine kinase in tumorigenesis and metastasis.Future Oncol, 3: 441–448, 2007.
7.
CampE.R., LiuW., FanF., YangA., SomcioR., EllisL.M.: RON, a tyrosine kinase receptor involved in tumor progression and metastasis.Ann Surg Oncol, 12: 273–281, 2005.
8.
WangM.H., YaoH.P., ZhouY.Q.: Oncogenesis of RON receptor tyrosine kinase: a molecular target for malignant epithelial cancers.Acta Pharmacol Sin, 27: 641–650, 2006.
9.
WangM.H., WangD., ChenY.Q.: Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase.Carcinogenesis, 24: 1291–1300, 2003.
10.
WaghP.K., PeaceB.E., WaltzS.E.: Met-related receptor tyrosine kinase Ron in tumor growth and metastasis.Adv Cancer Res, 100: 1–33, 2008.
11.
Danilkovitch-MiagkovaA.: Oncogenic signaling pathways activated by RON receptor tyrosine kinase.Curr Cancer Drug Targets, 3: 31–40, 2003.
12.
LeeC.T., ChowN.H., SuP.F., LinS.C., LinP.C., LeeJ.C.: The prognostic significance of RON and MET coexpression in patients with colorectal cancer.Dis Colon Rectum, 51: 1268–1274, 2008.
13.
MaggioraP., MarchioS., StellaM.C., GiaiM., BelfioreA., De BortoliM., Di RenzoM.F., CostantinoA., SismondiP., ComoglioP.M.: Overexpression of the RON gene in human breast carcinoma.Oncogene, 16: 2927–2933, 1998.
14.
WillettC.G., WangM.H., EmanuelR.L., GrahamS.A., SmithD.I., ShridharV., SugarbakerD.J., SundayM.E.: Macrophage-stimulating protein and its receptor in non-small cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.Am J Respir Cell Mol Biol, 18: 489–496, 1998.
15.
MaggioraP., LorenzatoA., FracchioliS., CostaB., CastagnaroM., ArisioR., KatsarosD., MassobrioM., ComoglioP.M., Flavia Di RenzoM.: The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness.Exp Cell Res, 288: 382–389, 2003.
16.
ThomasR.M., ToneyK., Fenoglio-PreiserC., Revelo-PenafielM.P., HingoraniS.R., TuvesonD.A., WaltzS.E., LowyA.M.: The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression.Cancer Res, 67: 6075–6082, 2007.
17.
OkinoT., EgamiH., OhmachiH., TakaiE., TamoriY., NakagawaA., NakanoS., SakamotoO., SudaT., OgawaM.: Immunohistochemical analysis of distribution of RON receptor tyrosine kinase in human digestive organs.Dig Dis Sci, 46: 424–429, 2001.
18.
ChengH.L., LiuH.S., LinY.J., ChenH.H., HsuP.Y., ChangT.Y., HoC.L., TzaiT.S., ChowN.H.: Coexpression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder.Br J Cancer, 92: 1906–1914, 2005.
19.
ThobeM.N., GurusamyD., WaltzS.E.: The Ron receptor tyrosine kinase positively regulates angiogenic chemokine production in prostate cancer cells.Oncogene, 29: 214–226, 2010.
20.
PeaceB.E., Toney-EarleyK., CollinsM.H., WaltzS.E.: Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer.Cancer Res, 65: 1285–1293, 2005.
21.
American Joint Committee on Cancer (AJCC):Cancer staging manual, ed 6, revised, pp 113–123, Lippincott-Raven, Philadelphia, 2002.
22.
SongG., OuyangG., BaoS.: The activation of Akt/PKB signaling pathway and cell survival.J Cell Mol Med, 9(1): 59–71, 2005.
23.
SchultzD.R., HarringtonW.J.Jr.: Apoptosis: programmed cell death at a molecular level.Semin Arthritis Rheum, 32: 345–369, 2003.
24.
GranaX., ReddyE.P.: Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs).Oncogene, 11: 211–219, 1995.
25.
CargnelloM., RouxP.P.: Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.Microbiol Mol Biol Rev, 75: 50–83, 2011.
26.
KeshetY., SegerR.: The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions.Methods Mol Biol, 661: 3–38, 2010.
27.
PratilasC.A., SolitD.B.: Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response.Clin Cancer Res, 16: 3329–3334, 2010.
28.
HaagensonK.K., WuG.S.: Mitogen activated protein kinase phosphatases and cancer.Cancer Biol Ther, 9: 337–340, 2010.
29.
DattaS.R., DudekH., TaoX., MastersS., FuH., GotohY., GreenbergM.E.: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.Cell, 91: 231–241, 1997.
30.
DanilkovitchA., SkeelA., LeonardE.J.: Macrophage-stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism.Exp Cell Res, 248: 575–582, 1999.
31.
XiaoZ.Q., ChenY.Q., WangM.H.: Requirement of both tyrosine residues 1330 and 1337 in the C-terminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration.Biochem Biophys Res Commun, 267: 669–675, 2000.
32.
BardelliA., LongatiP., GramagliaD., BasilicoC., TamagnoneL., GiordanoS., BallinariD., MichieliP., ComoglioP.M.: Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth.Proc Natl Acad Sci USA, 95: 14379–14383, 1998.
33.
MorinP.J.: Beta-catenin signaling and cancerBioEssays, 21: 1021–1030, 1999.
34.
BullinosL.C., LevineA.J.: The role of beta-catenin in cell adhesion, signal transduction and cancerCurr Opin Oncol, 10: 81–87, 1998.
35.
Danilkovitch-MiagkovaA., MiagkovA., SkeelA., NakaigawaN., ZbarB., LeonardE.J.: Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of β-catenin pathway.Mol Cell Biol, 21: 5857–5868, 2001.
36.
XuX.M., ZhouY.Q., WangM.H.: Mechanisms of cytoplasmic β-catenin accumulation and its involvement in tumorigenic activities mediated by oncogenic splicing variant of the receptor originated from nantes tyrosine kinase.J Biol Chem, 280: 25087–25094, 2005.
ChairoungduaA., SmithD.L., PochardP., HullM., CaplanM.J.: Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling.J Cell Biol, 190: 1079–1091, 2010.
39.
DeCarolisN.A., WhartonK.A.Jr., EischA.J.: Which way does the Wnt blow? Exploring the duality of canonical Wnt signaling on cellular aging.Bioessays, 30: 102–106, 2008.
