Falgàs, Aïda

Universitat Autònoma de Barcelona. Facultat de Biociències

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Stabilization of β‐catenin in the Wnt pathway and its implication in gastrointestinal cancersAïda Falgàs Comamala. Autonomous University of Barcelona. Biomedical Sciences DegreeTh i l W hIntroduction Aims and methodology Signalling by the Wnt family of secreted glycoprotein is one of the fundamental mechanisms that directcell proliferation, cell polarity, and cell fate determination during embryonic development and tissuehomeostasis. As a result, mutations in the Wnt pathway are often linked to human birth defects,cancer, and other diseases.A critical and heavily studied Wnt pathway is the canonical Wnt pathway, which functions by regulatingthe amount of the transcriptional coactivator β‐catenin. Aberrant canonical Wnt pathway is widelyimplicated in gastrointestinal cancers. All mechanisms deregulated in these tumour types provide aframework for understanding the complexities faced in attempting leverage this pathway in the clinic.The aim of this project was to study the canonical Wnt pathway and its physiological role in the renewal ofthe intestinal epithelium. This is essential to better understand the pathway alterations that can cause thedevelopment of certain intestinal epithelium cancers.The methodology used was a scientific literature search on PubMed database. Keywords used were“canonical Wnt pathway” and “gastrointestinal cancers”. This search was carried out through the selection ofrecent papers and reviews, according to their quality and date of publication.e canon ca   nt pat wayIn the absence of Wnt signals, cytoplasmic β‐cateninreleased from adherents junctions, is constantlydegraded by the action of the multiproteic complex,which is composed of the scaffolding protein Axin, thetumour suppressor adenomatous polyposis coli geneproduct (APC), casein kinase 1 (CK1) and glycogensynthase kinase 3 (GSK3).CK1 and GSK3 sequentially phosphorylate the N‐terminalregion of β‐catenin, resulting in β‐catenin recognition byβ‐Trcp, an E3 ubiquitin ligase subunit, and subsequent β‐Wnt/β‐catenin pathway is activated when a Wntligand binds Frizzled (Fz) receptor and its co‐receptor low‐density lipoprotein receptor‐related protein 5 or 6 (LRP5/6). The formation ofthe complex Wnt‐Fz‐LRP5/6, together with therecruitment of the scaffolding proteinDishevelled (Dvl), results in LRP5/6phosphorylation and the recruitment of the Axincomplex to the receptors.The canonical Wnt pathway controls the stability of β‐catenin. β‐catenin has a dual role in the cell in the cell membrane as part of adherents junctions and in the nucleus as a transcriptional co‐activatorFig. 1:  Fig. 2: Function of the canonical Wnt pathway in the renewal of the intestinal epitheliumcatenin ubiquitination and proteasomal degradation.This continual elimination of β‐catenin prevents β‐catenin from reaching the nucleus. Wnt target genesexpression is repressed by Groucho/TLE interaction withthe DNA‐bound T cell factor/lymphoid enhancer factor(TCF/LEF) family of proteins.The canonical Wnt signalling not onlyMacDonald BT, Tamal K, He X (2009)MacDonald BT, Tamal K, He X (2009)This event leads to inhibition of the Axin‐mediated β‐catenin phosphorilation and therebyto the stabilization of β‐catenin, whichaccumulates and translocates to the nucleus tointeract with TCF/LEF transcription factors andactivatesWnt target gene expression.I th i t ti l ith li lif ti t d diff ti t d ill ll f ti h t f ll th t iFi 3Normal intestinal cryptHyperactivation of the canonical Wnt pathway in the development of gastrointestinal tumors? There are common mechanisms by which the Wnt/β‐catenin pathway is upregulated in gastrointestinal cancer (Fig. 4):(A) Loss‐of‐function mutations in APC lead to a breakdown of the destruction complex and cause aconstitutive expression of Wnt/β‐catenin‐dependent genes.(B) Gain‐of‐function mutations in β‐catenin, often occurring in exon 3, prevent its N‐terminalfeatures in many developmentalprocesses; in some self‐renewingtissues, such as intestinal epithelium, itremains essential throughout life.n e n es na ep e um, pro era ng cryp precursors an eren a e v us ce s orm a con guous s ee o ce s a sin perpetual upward motion. Intestinal stem cells, which produce the transit‐amplifying progenitor cells, reside near the bottomof the crypt and escape this flow.Evidence suggests that Wnt signalling is required for the establishment of the progenitor compartment in the intestinalepithelium.g.   : Differentiated cellsTransient amplifying progenitorsIntestinal stem cells (ISC) Adaptation of  Voloshanenko O, Erdmann G,  Dubash TD et al. (2013)CRC HCC% of human tumours containing mutations in key members of Wnt/β‐catenin pathway90% 18‐44%Wnt/β‐catenin pathway members mutated most often 80% APC,10% β‐catenin3‐44% β‐catenin,5‐25% AxinCrosstalk with other signalling pathways  Notch, Hh TGF‐β, HGF/METphosphorylation thus averting its ubiquitination and degradation.(C) Overexpression of Fz receptors or Wnt ligands can lead to increased activation of the pathway.(D) Underexpression of secreted inhibitors of the pathway (secreted frizzled—related proteins, sFRPs) canalso lead to increased sensitivity to Wnt ligands and increased pathway activation.? Interactions with other signalling pathways influence on the activation of the Wnt/β‐catenin pathway, such as Notch,Hedgehog (Hh) and TGF‐β.Two types of gastrointestinal cancerswith high mutation rate in keymembers of the canonical Wntpathway: the colorectal carcinoma(CRC) and the hepatocellularcarcinoma (HCC).Table 1:P t ti l th i C l iAdaptation of White B, Chien A and Dawson D (2012)White B, Chien A and Dawson D (2012)CRCAdaptation of Fearon and Vogelstein (1990) Fig.  4 ? CRC is the most well studied cancercaused by overactivation of the Wnt/β‐catenin. The canonical Wnt pathway isfrequently the first altered pathway in thistype of gastrointestinal cancer (Fig. 5).? HCC is not as well studied as the CRC inthe carcinogenesis progression.Fig.  5 o en a erap es onc us ons‐ The canonical Wnt pathway is physiologically active in different tissues, such as intestinal epithelium, torenew different cell types throughout life.‐ Mutations in APC, β‐catenin or overexpression of Wnt ligands are three alterations that cause constitutiveactivation of the Wnt/β‐catenin pathway and originate gastrointestinal cancers.‐ Two examples of gastrointestinal cancers are the CRC and the HCC. Within cases of sporadic CRC, mostcontain mutations in the APC gene, while HCC cases contain mutations mainly in the β‐catenin or Axin protein.‐ In conclusion, gastrointestinal cancers caused by aberrant activation of the canonical Wnt signallingcurrently do not have a safe and effective treatment.At present there are no inhibitors clinically approved for the Wnt/β‐catenin pathway to treat tumors, as example the CRC and the HCC.There are several possible hypotheses to explain the absence of an effective therapy in these tumors:1. Involvement of the Wnt/β‐catenin pathway in the potential maintaining of stem cells.2. Heterogeneity of Wnt/β‐catenin signalling in normal tissues and in tumors. 3. Uncertainty about its efficacy and toxicity in the individual. Studies indicate that some phytochemicals and the active form of vitamin D can inhibit or modulate Wnt/β catenin signalling pathway. 

Stabilization of β-catenin in the Wnt pathway and its implication in gastrointestinal cancers

http://ddd.uab.cat/pub/tfg/2014/126433/TFG_AidaFalgasComamala.pdf

Stabilization of β-catenin in the Wnt pathway and its implication in gastrointestinal cancers

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