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Role of the Wnt Signaling Pathway and Lung Cancer

      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.
      • Willert K
      • Jones KA
      Wnt signaling: is the party in the nucleus?.
      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.
      • Jass JR
      • Barker M
      • Fraser L
      • Walsh MD
      • Whitehall VL
      • Gabrielli B
      • Young J
      • Leggett BA
      APC mutation and tumour budding in colorectal cancer.
      • Mikesch JH
      • Steffen B
      • Berdel WE
      • Serve H
      • Muller-Tidow C
      The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia.
      • Turashvili G
      • Bouchal J
      • Burkadze G
      • Kolar Z
      Wnt signaling pathway in mammary gland development and carcinogenesis.
      • Yardy GW
      • Brewster SF
      Wnt signaling and prostate cancer.
      • Thompson MD
      • Monga SP
      WNT/β-catenin signaling in liver health and disease.

      WNT SIGNALING

      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.
      • Widelitz R
      Wnt signaling through canonical and non-canonical pathways: recent progress.
      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.
      • Pongracz JE
      • Stockley RA
      Wnt signalling in lung development and diseases.
      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 Cancer
      Pathway ComponentType of Cancer
      Increased Wnt-1Prostate,
      • Chen 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.
      Head and Neck,
      • Rhee 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.
      Breast
      • Wong 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.
      Increased Wnt-2Breast
      • Watanabe 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.
      Decreased Wnt5aColorectal,
      • Dejmek 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.
      Neuroblastoma,
      • Blanc E
      • Goldschneider D
      • Douc-Rasy S
      • Benard J
      • Raguenez G
      Wnt-5a gene expression in malignant human neuroblasts.
      Thyroid,
      • Kremenevskaja N
      • von Wasielewski R
      • Rao AS
      • Schofl C
      • Andersson T
      • Brabant G
      Wnt-5a has tumor suppressor activity in thyroid carcinoma.
      Breast
      • Jonsson M
      • Dejmek J
      • Bendahl PO
      • Andersson T
      Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas.
      Increased Wnt7aColorectal,
      • Kirikoshi H
      • Katoh M
      Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer.
      Gastric,
      • Kirikoshi H
      • Katoh M
      Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer.
      Endometrial,
      • Bui 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.
      Decreased Wnt7aLung
      • Winn 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.
      • Calvo 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.
      Increased DVLBreast,
      • Turashvili G
      • Bouchal J
      • Burkadze G
      • Kolar Z
      Wnt signaling pathway in mammary gland development and carcinogenesis.
      Lung,
      • Uematsu 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.
      Mesothelioma
      • Uematsu 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.
      Increased LRP5/LRP6Colorectal
      • Watanabe 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.
      Increased Fzd2Gastric
      • Kirikoshi H
      • Sekihara H
      • Katoh M
      Expression profiles of 10 members of Frizzled gene family in human gastric cancer.
      Increased Fzd3Leukemia
      • Lu 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.
      Increased Fzd5Kidney
      • Janssens N
      • Andries L
      • Janicot M
      • Perera T
      • Bakker A
      Alteration of frizzled expression in renal cell carcinoma.
      Increased Fzd7Liver
      • Merle 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.
      Increased Fzd8Gastric
      • Kirikoshi H
      • Sekihara H
      • Katoh M
      Expression profiles of 10 members of Frizzled gene family in human gastric cancer.
      Increased Fzd9Astrocytoma,
      • Zhang Z
      • Schittenhelm J
      • Guo K
      • Buhring HJ
      • Trautmann K
      • Meyermann R
      • Schluesener HJ
      Upregulation of frizzled 9 in astrocytomas.
      Gastric
      • Kirikoshi H
      • Sekihara H
      • Katoh M
      Expression profiles of 10 members of Frizzled gene family in human gastric cancer.
      Decreased sFRPLiver,
      • Shih YL
      • Hsieh CB
      • Lai HC
      • Yan MD
      • Hsieh TY
      • Chao YC
      • Lin YW
      SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway.
      Breast,
      • Turashvili G
      • Bouchal J
      • Burkadze G
      • Kolar Z
      Wnt signaling pathway in mammary gland development and carcinogenesis.
      Bladder,
      • Marsit CJ
      • Karagas MR
      • Schned A
      • Kelsey KT
      Carcinogen exposure and epigenetic silencing in bladder cancer.
      Head and Neck,
      • Marsit 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.
      Leukemia,
      • Liu 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.
      Mesothelioma,
      • Lee 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.
      Colorectal
      • Qi J
      • Zhu YQ
      • Luo J
      • Tao WH
      Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor.
      Increased DVLBreast,
      • Turashvili G
      • Bouchal J
      • Burkadze G
      • Kolar Z
      Wnt signaling pathway in mammary gland development and carcinogenesis.
      Lung,
      • Uematsu 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.
      Mesothelioma
      • Uematsu 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.
      Decreased APCGastrointestinal,
      • Nielsen 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.
      Breast,
      • Jeronimo 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.
      Kidney
      • Sansom OJ
      • Griffiths DF
      • Reed KR
      • Winton DJ
      • Clarke AR
      Apc deficiency predisposes to renal carcinoma in the mouse.
      Decreased AxinOral,
      • Zhou CX
      • Gao Y
      Frequent genetic alterations and reduced expression of the Axin1 gene in oral squamous cell carcinoma: involvement in tumor progression and metastasis.
      Liver,
      • Laurent-Puig P
      • Zucman-Rossi J
      Genetics of hepatocellular tumors.
      Lung
      • Xu 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.
      Increased β-cateninOvarian,
      • Willner J
      • Wurz K
      • Allison KH
      • Galic V
      • Garcia RL
      • Goff BA
      • Swisher EM
      Alternate molecular genetic pathways in ovarian carcinomas of common histological types.
      Hepatoblastoma,
      • Yamaoka H
      • Ohtsu K
      • Sueda T
      • Yokoyama T
      • Hiyama E
      Diagnostic and prognostic impact of β-catenin alterations in pediatric liver tumors.
      Kidney
      • Satoh 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.
      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.
      • Widelitz R
      Wnt signaling through canonical and non-canonical pathways: recent progress.
      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 challenging
      • He X
      • Axelrod JD
      A WNTer wonderland in Snowbird.
      (Figure 1).
      Figure thumbnail gr1
      FIGURE 1Wnt/β-catenin signaling. (A). Canonical pathway. (B). Noncanonical pathway.
      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.
      • Quaiser T
      • Anton R
      • Kuhl M
      Kinases and G proteins join the Wnt receptor complex.
      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.
      • Kikuchi A
      • Yamamoto H
      • Kishida S
      Multiplicity of the interactions of Wnt proteins and their receptors.

      WNT SIGNALING IN NORMAL LUNG DEVELOPMENT

      Wnt signaling appears to regulate cell fate and differentiation in early embryogenesis through several components that are present in the developing lung.
      • Shannon JM
      • Hyatt BA
      Epithelial-mesenchymal interactions in the developing lung.
      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.
      • Pongracz JE
      • Stockley RA
      Wnt signalling in lung development and diseases.
      Wnt 7b has been shown to be regulated by Thyroid Transcription Factor-1, which is important for differentiation of alveolar epithelial cells.
      • Minoo P
      • Hamdan H
      • Bu D
      • Warburton D
      • Stepanik P
      • deLemos R
      TTF-1 regulates lung epithelial morphogenesis.
      Other Wnt pathway components, such as Frizzled and Tcf, have been detected in specific patterns in the developing lung.
      • Tebar 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.
      Wnt 7b null mice have hypoplastic lungs and impaired alveolar type I cell differentiation.
      • Shu W
      • Jiang YQ
      • Lu MM
      • Morrisey EE
      Wnt7b regulates mesenchymal proliferation and vascular development in the lung.
      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.
      • Li C
      • Xiao J
      • Hormi K
      • Borok Z
      • Minoo P
      Wnt5a participates in distal lung morphogenesis.
      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.
      • Mucenski 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.
      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.
      • Karner C
      • Wharton KA
      • Carroll TJ
      Apical-basal polarity, Wnt signaling and vertebrate organogenesis.

      WNT SIGNALING AND LUNG CANCER

      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.
      • Daniel VC
      • Peacock CD
      • Watkins DN
      Developmental signalling pathways in lung cancer.
      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.
      • Winn 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.
      • Winn 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.
      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.
      • Mazieres J
      • He B
      • You L
      • Xu Z
      • Jablons DM
      Wnt signaling in lung cancer.
      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.
      • Kim J
      • You L
      • Xu Z
      • Kuchenbecker K
      • Raz D
      • He B
      • Jablons D
      Wnt inhibitory factor inhibits lung cancer cell growth.
      APC and sFRP1 are also methylated in lung adenocarcinoma, often concomitantly with WIF-1.
      • Tang 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.
      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.
      • Dehan 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.
      DKK1, an antagonist of Wnt signaling, is expressed in NSCLC cell lines, while sFRPs are downregulated.
      • Mazieres J
      • He B
      • You L
      • Xu Z
      • Jablons DM
      Wnt signaling in lung cancer.
      • Forget 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.
      These findings suggest roles for Wnt pathway components in tumorigenesis, though more work is needed to clarify the biological effects of pathway disruption.

      WNT SIGNALING PATHWAY AS A THERAPEUTIC TARGET

      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.
      • He 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.
      Interference with Wnt 1 signaling by siRNA or antibody induces apoptosis in cancer cells and inhibits tumor growth in vivo.
      • You L
      • Kim J
      • He B
      • Xu Z
      • McCormick F
      • Jablons DM
      Wnt-1 signal as a potential cancer therapeutic target.
      siRNA for Wnt 2 downregulates β-catenin and induces apoptosis in NSCLC.
      • You 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.
      Restoration of Wnt 7a expression has been shown to reverse transformation in NSCLC and may be one approach to therapy through Wnt signaling.
      • Winn 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.
      Reduction of Disheveled overexpression by siRNA leads to a decrease in β-catenin expression and Tcf transcription activity in NSCLC.
      • Uematsu 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.
      A small molecule inhibitor, ICG-001, antagonizes β-catenin/Tcf transcription activation and downregulates β-catenin/Tcf responsive genes.
      • Emami 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].
      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.
      • Emami 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].
      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.
      • Karner C
      • Wharton KA
      • Carroll TJ
      Apical-basal polarity, Wnt signaling and vertebrate organogenesis.
      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.

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