research progression present

8/14/2019 Research Progression Present

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Research progression21/07/2009

By

Tanan Bejrananda, MD.


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Wnt signaling and CA


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Wnt signaling in CA colon

Outline

Background

Research question

Study design

Material and method


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Background

Identified through genetic studies indrosophila.

Highly conserved in evolution and are very

important in animal development


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Wnts

Wnt proteins released from or presented on thesurface of signaling cells act on target cells bybinding to Frizzled (Fz)/LDL-related protein(LDR) complex at the cell surface.

Receptors Frizzled receptors, like GPCRs, are transmembrane

proteins that span 7 timesthe plasma membrane.

Their ligand-binding site is exposed outside the

surface of the cell. Their effector site extends into the cytosol.


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Wnt

Wnt proteins form a family of highlyconserved secreted signaling moleculesthat regulate cell-to-cell interactions during

embryogenesis. Insights into the mechanisms of Wnt action

have emerged from several systems:

genetics in Drosophila and Caenorhabditiselegans; biochemistry in cell culture andectopic gene expression inXenopus


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Wnt

Mutations in Wnt genes or Wnt pathwaycomponents lead to specificdevelopmental defects, while various

human diseases, including cancer, arecaused by abnormal Wnt signaling.


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As currently understood, Wnt proteins

bind to receptors of the Frizzled and LRPfamilies on the cell surface.

Through several cytoplasmic relaycomponents, the signal is transduced tobeta-catenin, which enters the nucleus

and forms a complex with TCF to activatetranscription of Wnt target genes


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Wnt pathway


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Ligands Their ligands are Wnt

proteins. These get

their name from two ofthe first to bediscovered, proteinsencoded by

wingless (wg) in

Drosophila and itshomolog

Int-1 in mice.


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Fz receptors transducesignals to intra-cellularproteins including Dsh,GSK-3, Axin, APC and

-catenin

Nuclear -catenininteracts with lymphoidenhancer-binding factor

1/T cell-specifictranscription factor(LEF/TCF) to affecttranscription.


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In vertebrates, Wntproteins are inhibited bydirect binding to eithersecreted frizzled-relatedprotein (SFRP) or Wntinhibitory factor (WIF).

SFRP is similar insequence to the cysteine-rich domain (CRD) of

Frizzled, one of the Wntreceptors.


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GSK-3b dependentphosphorylation,ubiquitination and

complex formation withthe proteins axin andAPC are important toregulate the cytoplasmicstability of beta-catenin

protein in the wnt-signaltransduction pathway


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Interaction with TCFtranscription factorsand the transactivation

domains of beta-catenin areinstrumental toactivate/derepress wnt-target genes in thenucleus.


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Complex formation with cadherins and alpha-catenin atthe plasma membrane is essential for the role of beta-catenin in cell adhesion.

In vertebrate development, loss of a single Wnt gene can

produce dramatic phenotypes that range from embryoniclethality and CNS abnormalities to kidney and limbdefects

These diverse phenotypes indicate that the Wnt pathway

has distinct transcriptional outputs.

In many cases, the cell, rather than the signal,determines the nature of the response, and up- or down-regulation of Wnt target genes is cell-type specific.


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WNT TARGET GENES ANDFEEDBACK LOOPS


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WNT SIGNALING IN CANCER

AND HUMAN DISEASE In adults, mis-regulation of the Wnt

pathway also leads to a variety of

abnormalities and degenerative diseases


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Current evidence indicates thatthe Wnt cascade is the singlemost dominant force incontrolling cell fate along thecrypt-villus axis.

In Tcf4 -/- neonatal mice, thevillus epithelial compartmentappears unaffected but thecrypt progenitor compartmentis entirely absent, implying that

physiological Wnt signalling isrequired for maintenance ofthe crypt progenitorphenotype.

From crypt physiology to colon cancer


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The Wnt pathway in colon cancer

The APC gene was originally discovered to bethe culprit in a hereditary cancer syndrometermed familial adenomatous polyposis (FAP).

FAP patients, inheriting one defective APCallele, develop large numbers of colon polyps, oradenomas, early in life.

Individual polyps are clonal outgrowths of

epithelial cells in which the second APC allele isinactivated.


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Mutational inactivation of APC leads to theinappropriate stabilization of b-catenin, implyingthat the absence of functional APC transforms

epithelial cells through activation of the Wntcascade.

In some cases of colorectal cancer in which APCis not mutated, the scaffolding protein axin 2 is

mutant, or activating (oncogenic) point mutationsin b-catenin remove its N-terminal Ser/Thrdestruction motif.


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Multiple studies have used a candidategene approach to address the nature ofthe Tcf4 target gene programme in

colorectal cancer.


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Title :

What are the relating of Wntsignalingwith Colorectal cancer in Thailand ?

Study Design :


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Primary outcome

Secondary outcome

Study Design : Material and


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Design



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Patient

- All patients with CA colon were admitted

between to in SongkhlanagarindHospital in Hadyai, Thailand.



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Exclusion criteria



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Data collection



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Statical study



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research progression present

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