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• W2035267253 abstract "The Wnt pathway plays an important role in development and in regulating adult stem cell systems. A variety of cellular processes are mediated by Wnt signaling, including proliferation, differentiation, survival, apoptosis and cell motility.1Willert K Jones KA Wnt signaling: is the party in the nucleus?.Genes Dev. 2006; 20: 1394-1404Crossref PubMed Scopus (488) Google Scholar Loss of regulation of these pathways can lead to tumorigenesis and the Wnt pathway has been implicated in the development of several types of cancers, including colon, lung, leukemia, breast, thyroid, and prostate.2Jass JR Barker M Fraser L Walsh MD Whitehall VL Gabrielli B Young J Leggett BA APC mutation and tumour budding in colorectal cancer.J Clin Pathol. 2003; 56: 69-73Crossref PubMed Scopus (133) Google Scholar, 3Mikesch JH Steffen B Berdel WE Serve H Muller-Tidow C The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia.Leukemia. 2007; PubMed Google Scholar, 4Turashvili G Bouchal J Burkadze G Kolar Z Wnt signaling pathway in mammary gland development and carcinogenesis.Pathobiology. 2006; 73: 213-223Crossref PubMed Scopus (155) Google Scholar, 5Yardy GW Brewster SF Wnt signaling and prostate cancer.Prostate Cancer Prostatic Dis. 2005; 8: 119-126Crossref PubMed Scopus (120) Google Scholar, 6Thompson MD Monga SP WNT/β-catenin signaling in liver health and disease.Hepatology. 2007; 45: 1298-1305Crossref PubMed Scopus (380) Google Scholar Wnts are a family of secreted glycoproteins with varying expression patterns and a range of functions. Four signaling pathways are typically described for Wnt proteins. The canonical Wnt-β catenin pathway, through which β-catenin dependent activity occurs, the polar cell polarity (PCP) pathway, involving activation of AP1 through JNK, an atypical receptor tyrosine kinase (RTK) pathway, and the Ca2+ pathway, which activates protein kinase C and affects cell adhesion.7Widelitz R Wnt signaling through canonical and non-canonical pathways: recent progress.Growth Factors. 2005; 23: 111-116Crossref PubMed Scopus (168) Google Scholar In the unstimulated canonical pathway, β-catenin is phosphorylated by glycogen synthase kinase (GSK-3) in a complex that includes adenomatous polyposis coli (APC) and axin.8Pongracz JE Stockley RA Wnt signalling in lung development and diseases.Respir Res. 2006; 7: 15Crossref PubMed Scopus (169) Google Scholar Phosphorylation targets β-catenin for ubiquitin-mediated degredation and results in decreased levels of cytosolic β-catenin (Table 1).TABLE 1Dysregulation of Wnt Pathway in CancerPathway ComponentType of CancerIncreased Wnt-1Prostate,32Chen G Shukeir N Potti A Sircar K Aprikian A Goltzman D Rabbani SA Up-regulation of Wnt-1 and β-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications.Cancer. 2004; 101: 1345-1356Crossref PubMed Scopus (244) Google Scholar Head and Neck,33Rhee CS Sen M Lu D Wu C Leoni L Rubin J Corr M Carson DA Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas.Oncogene. 2002; 21: 6598-6605Crossref PubMed Scopus (174) Google Scholar Breast34Wong SC Lo SF Lee KC Yam JW Chan JK Wendy Hsiao WL Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours.J Pathol. 2002; 196: 145-153Crossref PubMed Scopus (132) Google ScholarIncreased Wnt-2Breast35Watanabe O Imamura H Shimizu T Kinoshita J Okabe T Hirano A Yoshimatsu K Konno S Aiba M Ogawa K Expression of twist and wnt in human breast cancer.Anticancer Res. 2004; 24: 3851-3856PubMed Google ScholarDecreased Wnt5aColorectal,36Dejmek J Dejmek A Safholm A Sjolander A Andersson T Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis.Cancer Res. 2005; 65: 9142-9146Crossref PubMed Scopus (160) Google Scholar Neuroblastoma,37Blanc E Goldschneider D Douc-Rasy S Benard J Raguenez G Wnt-5a gene expression in malignant human neuroblasts.Cancer Lett. 2005; 228: 117-123Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Thyroid,38Kremenevskaja N von Wasielewski R Rao AS Schofl C Andersson T Brabant G Wnt-5a has tumor suppressor activity in thyroid carcinoma.Oncogene. 2005; 24: 2144-2154Crossref PubMed Scopus (224) Google Scholar Breast39Jonsson M Dejmek J Bendahl PO Andersson T Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas.Cancer Res. 2002; 62: 409-416PubMed Google ScholarIncreased Wnt7aColorectal,40Kirikoshi H Katoh M Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer.Int J Oncol. 2002; 21: 895-900PubMed Google Scholar Gastric,40Kirikoshi H Katoh M Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer.Int J Oncol. 2002; 21: 895-900PubMed Google Scholar Endometrial,41Bui TD Zhang L Rees MC Bicknell R Harris AL Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma.Br J Cancer. 1997; 75: 1131-1136Crossref PubMed Scopus (110) Google ScholarDecreased Wnt7aLung20Winn RA Marek L Han SY Rodriguez K Rodriguez N Hammond M Van Scoyk M Acosta H Mirus J Barry N Bren-Mattison Y Van Raay TJ Nemenoff RA Heasley LE Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation.J Biol Chem. 2005; 280: 19625-19634Crossref PubMed Scopus (130) Google Scholar, 42Calvo R West J Franklin W Erickson P Bemis L Li E Helfrich B Bunn P Roche J Brambilla E Rosell R Gemmill RM Drabkin HA Altered HOX and WNT7A expression in human lung cancer.Proc Natl Acad Sci U S A. 2000; 97: 12776-12781Crossref PubMed Scopus (185) Google ScholarIncreased DVLBreast,4Turashvili G Bouchal J Burkadze G Kolar Z Wnt signaling pathway in mammary gland development and carcinogenesis.Pathobiology. 2006; 73: 213-223Crossref PubMed Scopus (155) Google Scholar Lung,30Uematsu K He B You L Xu Z McCormick F Jablons DM Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression.Oncogene. 2003; 22: 7218-7221Crossref PubMed Scopus (271) Google Scholar Mesothelioma30Uematsu K He B You L Xu Z McCormick F Jablons DM Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression.Oncogene. 2003; 22: 7218-7221Crossref PubMed Scopus (271) Google ScholarIncreased LRP5/LRP6Colorectal43Watanabe T Kobunai T Toda E Kanazawa T Kazama Y Tanaka J Tanaka T Yamamoto Y Hata K Kojima T Yokoyama T Konishi T Okayama Y Sugimoto Y Oka T Sasaki S Ajioka Y Muto T Nagawa H Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray.Clin Cancer Res. 2007; 13: 415-420Crossref PubMed Scopus (51) Google ScholarIncreased Fzd2Gastric44Kirikoshi H Sekihara H Katoh M Expression profiles of 10 members of Frizzled gene family in human gastric cancer.Int J Oncol. 2001; 19: 767-771PubMed Google ScholarIncreased Fzd3Leukemia45Lu D Zhao Y Tawatao R Cottam HB Sen M Leoni LM Kipps TJ Corr M Carson DA Activation of the Wnt signaling pathway in chronic lymphocytic leukemia.Proc Natl Acad Sci U S A. 2004; 101: 3118-3123Crossref PubMed Scopus (334) Google ScholarIncreased Fzd5Kidney46Janssens N Andries L Janicot M Perera T Bakker A Alteration of frizzled expression in renal cell carcinoma.Tumour Biol. 2004; 25: 161-171Crossref PubMed Scopus (36) Google ScholarIncreased Fzd7Liver47Merle P Kim M Herrmann M Gupte A Lefrancois L Califano S Trepo C Tanaka S Vitvitski L de la Monte S Wands JR Oncogenic role of the frizzled-7/β-catenin pathway in hepatocellular carcinoma.J Hepatol. 2005; 43: 854-862Abstract Full Text Full Text PDF PubMed Scopus (127) Google ScholarIncreased Fzd8Gastric44Kirikoshi H Sekihara H Katoh M Expression profiles of 10 members of Frizzled gene family in human gastric cancer.Int J Oncol. 2001; 19: 767-771PubMed Google ScholarIncreased Fzd9Astrocytoma,48Zhang Z Schittenhelm J Guo K Buhring HJ Trautmann K Meyermann R Schluesener HJ Upregulation of frizzled 9 in astrocytomas.Neuropathol Appl Neurobiol. 2006; 32: 615-624Crossref PubMed Scopus (32) Google Scholar Gastric44Kirikoshi H Sekihara H Katoh M Expression profiles of 10 members of Frizzled gene family in human gastric cancer.Int J Oncol. 2001; 19: 767-771PubMed Google ScholarDecreased sFRPLiver,49Shih YL Hsieh CB Lai HC Yan MD Hsieh TY Chao YC Lin YW SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway.Int J Cancer. 2007; Google Scholar Breast,4Turashvili G Bouchal J Burkadze G Kolar Z Wnt signaling pathway in mammary gland development and carcinogenesis.Pathobiology. 2006; 73: 213-223Crossref PubMed Scopus (155) Google Scholar Bladder,50Marsit CJ Karagas MR Schned A Kelsey KT Carcinogen exposure and epigenetic silencing in bladder cancer.Ann N Y Acad Sci. 2006; 1076: 810-821Crossref PubMed Scopus (44) Google Scholar Head and Neck,51Marsit CJ McClean MD Furniss CS Kelsey KT Epigenetic inactivation of the SFRP genes is associated with drinking, smoking and HPV in head and neck squamous cell carcinoma.Int J Cancer. 2006; 119: 1761-1766Crossref PubMed Scopus (93) Google Scholar Leukemia,52Liu TH Raval A Chen SS Matkovic JJ Byrd JC Plass C CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia.Cancer Res. 2006; 66: 653-658Crossref PubMed Scopus (104) Google Scholar Mesothelioma,53Lee AY He B You L Dadfarmay S Xu Z Mazieres J Mikami I McCormick F Jablons DM Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma.Oncogene. 2004; 23: 6672-6676Crossref PubMed Scopus (183) Google Scholar Colorectal54Qi J Zhu YQ Luo J Tao WH Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor.World J Gastroenterol. 2006; 12: 7113-7117Crossref PubMed Scopus (88) Google ScholarIncreased DVLBreast,4Turashvili G Bouchal J Burkadze G Kolar Z Wnt signaling pathway in mammary gland development and carcinogenesis.Pathobiology. 2006; 73: 213-223Crossref PubMed Scopus (155) Google Scholar Lung,30Uematsu K He B You L Xu Z McCormick F Jablons DM Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression.Oncogene. 2003; 22: 7218-7221Crossref PubMed Scopus (271) Google Scholar Mesothelioma55Uematsu K Kanazawa S You L He B Xu Z Li K Peterlin BM McCormick F Jablons DM Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of β-catenin.Cancer Res. 2003; 63: 4547-4551PubMed Google ScholarDecreased APCGastrointestinal,56Nielsen M Hes FJ Nagengast FM Weiss MM Mathus-Vliegen EM Morreau H Breuning MH Wijnen JT Tops CM Vasen HF Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis.Clin Genet. 2007; 71: 427-433Crossref PubMed Scopus (118) Google Scholar Breast,57Jeronimo C Monteiro P Henrique R Dinis-Ribeiro M Costa I Costa VL Filipe L Carvalho AL Hoque MO Pais I Leal C Teixeira MR Sidransky D Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions.Breast Cancer Res Treat. 2007; PubMed Google Scholar Kidney58Sansom OJ Griffiths DF Reed KR Winton DJ Clarke AR Apc deficiency predisposes to renal carcinoma in the mouse.Oncogene. 2005; 24: 8205-8210Crossref PubMed Scopus (7) Google ScholarDecreased AxinOral,59Zhou CX Gao Y Frequent genetic alterations and reduced expression of the Axin1 gene in oral squamous cell carcinoma: involvement in tumor progression and metastasis.Oncol Rep. 2007; 17: 73-79PubMed Google Scholar Liver,60Laurent-Puig P Zucman-Rossi J Genetics of hepatocellular tumors.Oncogene. 2006; 25: 3778-3786Crossref PubMed Scopus (292) Google Scholar Lung61Xu HT Wang L Lin D Liu Y Liu N Yuan XM Wang EH Abnormal β-catenin and reduced axin expression are associated with poor differentiation and progression in non-small cell lung cancer.Am J Clin Pathol. 2006; 125: 534-541Crossref PubMed Scopus (60) Google ScholarIncreased β-cateninOvarian,62Willner J Wurz K Allison KH Galic V Garcia RL Goff BA Swisher EM Alternate molecular genetic pathways in ovarian carcinomas of common histological types.Hum Pathol. 2007; 38: 607-613Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Hepatoblastoma,63Yamaoka H Ohtsu K Sueda T Yokoyama T Hiyama E Diagnostic and prognostic impact of β-catenin alterations in pediatric liver tumors.Oncol Rep. 2006; 15: 551-556PubMed Google Scholar Kidney64Satoh Y Nakadate H Nakagawachi T Higashimoto K Joh K Masaki Z Uozumi J Kaneko Y Mukai T Soejima H Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours.Br J Cancer. 2006; 95: 541-547Crossref PubMed Scopus (46) Google ScholarFzd, Frizzled; DVL, Disheveled; LRP, sFRP, Secreted Frizzled-Related Protein; APC, Adenomatous Polyposis Coli. Open table in a new tab Fzd, Frizzled; DVL, Disheveled; LRP, sFRP, Secreted Frizzled-Related Protein; APC, Adenomatous Polyposis Coli. Binding by the Wnt ligant to the frizzled (Fzd) receptors are complexed with low density lipoprotein receptor related protein (LRP) resulting in inhibition of the GSK-3/APC/Axin complex by Disheveled (Dvl). β-catenin is not phosphorylated by the complex and accumulates in the cytoplasm where it is translocated to the nucleus and regulates gene expression through a complex with Tcf and Lef.7Widelitz R Wnt signaling through canonical and non-canonical pathways: recent progress.Growth Factors. 2005; 23: 111-116Crossref PubMed Scopus (168) Google Scholar In the noncanonical pathways, signaling is conducted independent of β-catenin, though there may be similar components upstream of Fzd. The activity of different Wnt proteins is dependent on the receptor context, making strict classification of Wnts as canonical or noncanonical very challenging9He X Axelrod JD A WNTer wonderland in Snowbird.Development. 2006; 133: 2597-2603Crossref PubMed Scopus (19) Google Scholar (Figure 1). Fzd receptors are involved in canonical and noncanonical Wnt signaling by binding Wnt at a CRD region and have been shown to specify downstream activity through G-proteins. Binding of the LRP receptor to Fzd, however, occurs only in the canonical pathway.10Quaiser T Anton R Kuhl M Kinases and G proteins join the Wnt receptor complex.Bioessays. 2006; 28: 339-343Crossref PubMed Scopus (18) Google Scholar Other Wnt pathway receptors include atypical RTKs Ror and Ryk. Several ligands not structurally related to Wnt also influence the Wnt signaling pathway, including antagonists sFRP, DKK, SOST, and agonists Norrin and R-spondin.11Kikuchi A Yamamoto H Kishida S Multiplicity of the interactions of Wnt proteins and their receptors.Cell Signal. 2007; 19: 659-671Crossref PubMed Scopus (206) Google Scholar Wnt signaling appears to regulate cell fate and differentiation in early embryogenesis through several components that are present in the developing lung.12Shannon JM Hyatt BA Epithelial-mesenchymal interactions in the developing lung.Annu Rev Physiol. 2004; 66: 625-645Crossref PubMed Scopus (246) Google Scholar Wnt production may be specific to cell type, such as Wnt 2 in the mesenchyme, Wnt 7b in the epithelium, and Wnt 11 in both locations.8Pongracz JE Stockley RA Wnt signalling in lung development and diseases.Respir Res. 2006; 7: 15Crossref PubMed Scopus (169) Google Scholar Wnt 7b has been shown to be regulated by Thyroid Transcription Factor-1, which is important for differentiation of alveolar epithelial cells.13Minoo P Hamdan H Bu D Warburton D Stepanik P deLemos R TTF-1 regulates lung epithelial morphogenesis.Dev Biol. 1995; 172: 694-698Crossref PubMed Scopus (131) Google Scholar Other Wnt pathway components, such as Frizzled and Tcf, have been detected in specific patterns in the developing lung.14Tebar M Destree O de Vree WJ Ten Have-Opbroek AA Expression of Tcf/Lef and sFrp and localization of β-catenin in the developing mouse lung.Mech Dev. 2001; 109: 437-440Crossref PubMed Scopus (65) Google Scholar Wnt 7b null mice have hypoplastic lungs and impaired alveolar type I cell differentiation.15Shu W Jiang YQ Lu MM Morrisey EE Wnt7b regulates mesenchymal proliferation and vascular development in the lung.Development. 2002; 129: 4831-4842PubMed Google Scholar Wnt 5a is expressed in the lung epithelium and mesenchyme early development at the distal tips. Loss of Wnt 5a in mice results in increased proliferation in the epithelium and mesenchymal compartments, increased distal branching, and thickened interstitium.16Li C Xiao J Hormi K Borok Z Minoo P Wnt5a participates in distal lung morphogenesis.Dev Biol. 2002; 248: 68-81Crossref PubMed Scopus (225) Google Scholar Wnt 5a null mice have increased expression of Sonic Hedgehog, a tightly regulated protein involved in branching morphogenesis, suggesting that Wnt 5a interacts with other signaling pathways in lung development. However, a model using targeted deletion of β-catenin suggests that disruption of Wnt signaling leads to decreased branching morphogenesis.17Mucenski ML Nation JM Thitoff AR Besnard V Xu Y Wert SE Harada N Taketo MM Stahlman MT Whitsett JA β-catenin regulates differentiation of respiratory epithelial cells in vivo.Am J Physiol Lung Cell Mol Physiol. 2005; 289: L971-L979Crossref PubMed Scopus (131) Google Scholar Continued study is needed to clarify the role of Wnt signaling in branching morphogenesis. Wnt signaling may also play a role in apical-basal polarity and organogenesis, as changes in expression of polarity complex components have been found to affect Wnt signaling and the Wnt pathway itself may affect apical basal polarity.18Karner C Wharton KA Carroll TJ Apical-basal polarity, Wnt signaling and vertebrate organogenesis.Semin Cell Dev Biol. 2006; 17: 214-222Crossref PubMed Scopus (44) Google Scholar Much of the research done on the Wnt pathway and cancer has been done in colon tumors, however, recent work highlights a potentially significant role for Wnt pathway components in lung cancer. Wnt 1 and Wnt 2 are overexpressed in NSCLC and their inhibition leads to apoptosis.19Daniel VC Peacock CD Watkins DN Developmental signalling pathways in lung cancer.Respirology. 2006; 11: 234-240Crossref PubMed Scopus (49) Google Scholar Wnt 7a is of particular interest, as its re-expression has been reported to lead to growth inhibition of NSCLC cell lines through ERK5-dependent activation of Peroxisome Proliferator-Activated Receptor Gamma.20Winn RA Marek L Han SY Rodriguez K Rodriguez N Hammond M Van Scoyk M Acosta H Mirus J Barry N Bren-Mattison Y Van Raay TJ Nemenoff RA Heasley LE Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation.J Biol Chem. 2005; 280: 19625-19634Crossref PubMed Scopus (130) Google Scholar, 21Winn RA Van Scoyk M Hammond M Rodriguez K Crossno JT Heasley LE Nemenoff RA Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma.J Biol Chem. 2006; 281: 26943-26950Crossref PubMed Scopus (94) Google Scholar This pathway seems to be required for the maintenance of normal epithelial differentiation and represents noncanonical signaling by the Wnt pathway. Disheveled proteins are overexpressed in NSCLC and are a route for Wnt/Fzd activation of Rac and Rho, which are known to be involved in lung carcinogenesis.22Mazieres J He B You L Xu Z Jablons DM Wnt signaling in lung cancer.Cancer Lett. 2005; 222: 1-10Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar WIF-1, an antagonist of Wnt signaling, is silenced by promoter methylation in NSCLC and is able to inhibit cell growth in vitro and in vivo.23Kim J You L Xu Z Kuchenbecker K Raz D He B Jablons D Wnt inhibitory factor inhibits lung cancer cell growth.J Thorac Cardiovasc Surg. 2007; 133: 733-737Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar APC and sFRP1 are also methylated in lung adenocarcinoma, often concomitantly with WIF-1.24Tang M Torres-Lanzas J Lopez-Rios F Esteller M Sanchez-Cespedes M Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung.Int J Cancer. 2006; 119: 2603-2606Crossref PubMed Scopus (28) Google Scholar Evaluation of chromosomal aberrations and changes in gene expression in NSCLC found that WIF1, CTNNBIP1, and WISP2 (antagonists of the Wnt pathway) were underexpressed and LEF1 and Ruvbl1 (agonists) were overexpressed.25Dehan E Ben-Dor A Liao W Lipson D Frimer H Rienstein S Simansky D Krupsky M Yaron P Friedman E Rechavi G Perlman M Aviram-Goldring A Izraeli S Bittner M Yakhini Z Kaminski N Chromosomal aberrations and gene expression profiles in non-small cell lung cancer.Lung Cancer. 2007; 56: 175-184Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar DKK1, an antagonist of Wnt signaling, is expressed in NSCLC cell lines, while sFRPs are downregulated.22Mazieres J He B You L Xu Z Jablons DM Wnt signaling in lung cancer.Cancer Lett. 2005; 222: 1-10Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 26Forget MA Turcotte S Beauseigle D Godin-Ethier J Pelletier S Martin J Tanguay S Lapointe R The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types.Br J Cancer. 2007; 96: 646-653Crossref PubMed Scopus (132) Google Scholar These findings suggest roles for Wnt pathway components in tumorigenesis, though more work is needed to clarify the biological effects of pathway disruption. The Wnt pathway may play a significant role in lung tumor initiation and progression, thus providing opportunities for therapeutic intervention. Therapuetic interference with the Wnt pathway could be conducted at several levels. Restoration of SFRP4 function in cancer cells weakens Wnt signaling and induces apoptosis in NSCLC cell lines.27He B Lee AY Dadfarmay S You L Xu Z Reguart N Mazieres J Mikami I McCormick F Jablons DM Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in β-catenin-deficient human mesothelioma cells.Cancer Res. 2005; 65: 743-748PubMed Google Scholar Interference with Wnt 1 signaling by siRNA or antibody induces apoptosis in cancer cells and inhibits tumor growth in vivo.28You L Kim J He B Xu Z McCormick F Jablons DM Wnt-1 signal as a potential cancer therapeutic target.Drug News Perspect. 2006; 19: 27-31Crossref PubMed Scopus (28) Google Scholar siRNA for Wnt 2 downregulates β-catenin and induces apoptosis in NSCLC.29You L He B Xu Z Uematsu K Mazieres J Mikami I Reguart N Moody TW Kitajewski J McCormick F Jablons DM Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells.Oncogene. 2004; 23: 6170-6174Crossref PubMed Scopus (217) Google Scholar Restoration of Wnt 7a expression has been shown to reverse transformation in NSCLC and may be one approach to therapy through Wnt signaling.20Winn RA Marek L Han SY Rodriguez K Rodriguez N Hammond M Van Scoyk M Acosta H Mirus J Barry N Bren-Mattison Y Van Raay TJ Nemenoff RA Heasley LE Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation.J Biol Chem. 2005; 280: 19625-19634Crossref PubMed Scopus (130) Google Scholar Reduction of Disheveled overexpression by siRNA leads to a decrease in β-catenin expression and Tcf transcription activity in NSCLC.30Uematsu K He B You L Xu Z McCormick F Jablons DM Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression.Oncogene. 2003; 22: 7218-7221Crossref PubMed Scopus (271) Google Scholar A small molecule inhibitor, ICG-001, antagonizes β-catenin/Tcf transcription activation and downregulates β-catenin/Tcf responsive genes.31Emami KH Nguyen C Ma H Kim DH Jeong KW Eguchi M Moon RT Teo JL Kim HY Moon SH Ha JR Kahn M A small molecule inhibitor of β-catenin/CREB-binding protein transcription [corrected].Proc Natl Acad Sci U S A. 2004; 101: 12682-12687Crossref PubMed Scopus (650) Google Scholar The Wnt pathway, along with the Hedgehog pathway, is activated by smoke in bronchial epithelial cells and treatment with Sulindac, a Wnt pathway specific inhibitor, resulted in decreased tumor mass and volume in mice.31Emami KH Nguyen C Ma H Kim DH Jeong KW Eguchi M Moon RT Teo JL Kim HY Moon SH Ha JR Kahn M A small molecule inhibitor of β-catenin/CREB-binding protein transcription [corrected].Proc Natl Acad Sci U S A. 2004; 101: 12682-12687Crossref PubMed Scopus (650) Google Scholar This may be an opportunity for inhibition of early stage tumorigenesis in the lungs of smokers. Proper apical/basal polarity has been implicated in cell cycle control and cell-cell adhesion, both processes disrupted in tumorigenesis, and as the role of Wnt signaling in this process is clarified, interventions in this pathway that lead to restoration of apical basal polarity may be therapeutic options.18Karner C Wharton KA Carroll TJ Apical-basal polarity, Wnt signaling and vertebrate organogenesis.Semin Cell Dev Biol. 2006; 17: 214-222Crossref PubMed Scopus (44) Google Scholar Investigations into the role of Wnt signaling in the lung have clearly begun to elucidate the importance of this pathway in lung cancer, however, there is still much to be done. The participation of different Wnt proteins in different pathways complicates the determination of the effects of changes in Wnt expression, as does the presence of many levels of regulation along the pathway. The diversity of Wnt signaling, however, provides a bounty of opportunity for development of desperately needed targeted therapy for lung cancer." @default.
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• W2035267253 title "Role of the Wnt Signaling Pathway and Lung Cancer" @default.
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