The interaction between the Wnt –and Notch-pathways in colorectal cancer development by: John Grünberg The aim is to study the interaction between the.

Slides:

Advertisements

Similar presentations

The Notch-  -Secretase Pathway. Notch activation involves the proteolytic cleavage of the Notch ligand/receptor complex by  -secretase to release the.

Advertisements

Notch receptor and ligands Receptor isoforms: Notch 1-4 Ligands: jagged 1, jagged 2, delta1, delta2, delta 3, delta 4 Microenviroment of bone marrow.

Breast cancer affects over 200,000 new patients in the United States every year. One particularly challenging subtype is triple- negative breast cancer.

KRAS testing in colorectal cancer: an overview. 2 What is KRAS? KRAS is a gene that encodes one of the proteins in the epidermal growth factor receptor.

Advanced Cancer Topics Journal Review 4/16/2009 AD.

TLX, Wnt & neurogenesis.

Β-Catenin, Cancer, and G Proteins Not Just for Frizzleds Anymore Ming Yang et al. PNAS Maria Domenica Castellone et al. Science

CONTEXT SPECIFIC ROLE OF DEUBIQUITYLASE ENZYME, USP9X, IN HEAD AND NECK CANCER Devathri Nanayakkara Eskitis Institute for Drug Discovery Griffith University.

Supplemental figure 1: Correlation coefficients between signal intensities from biological replicates of wild.

Computational biology of cancer cell pathways Modelling of cancer cell function and response to therapy.

CENTRE FOR BIOTECHNOLOGY

Chromatin remodelling ATPase Brg1 is an essential factor for the maintenance of the intestinal crypt stem cell and adenoma formation Aliaksei Holik.

Inhibition of PDCD6 Induces Cell Proliferation and Reduces Apoptosis in Human Epithelial Ovarian Cancer Cells Yan Huang, Xiaohua Wu Department of Gynecology,

Smad3-dependent nuclear translocation of B-catenin is required for TGF-B1-induced proliferation of bone marrow- derivced adult human mesenchymal stem cells.

Wnt/β-catenin Signaling Pathway Prospective Target for Cancer Treatment Emelia E Conte 1, Jun Yin 2, Mei Zhang 2 Western Blot Introduction.

The early testosterone-induced actin reorganization in colon cancer is independent of iAR signalling control 15min30min60min + TAC control 15min 30min60min.

Chromatin remodelling ATPase Brg-1 is an essential factor for the maintenance of the intestinal crypt stem cell and adenoma formation Aliaksei Holik.

Targeting of reactive oxygen species can be a potential therapeutic strategy for cancer treatment Ying-Ray Lee 1, San-Yuan Chen 2, and Hau-Ren Chen 3 1.

Introduction Conclusions

Volume 141, Issue 5, Pages e1 (November 2011)

Ke Xu, Ph.D. Putuo Hospital and Cancer Institute,

WNT5A is a Key Regulator of the Epithelial-Mesenchymal Transition and Cancer Stem Cell Properties in Human Gastric Carcinoma Cells Pathobiology 2013;80:

MicroRNA-101 Inhibits Growth, Proliferation and Migration and Induces Apoptosis of Breast Cancer Cells by Targeting Sex-Determining Region Y-Box 2 Cell.

Nithya Krishnamurthy, Razelle Kurzrock Cancer Treatment Reviews

Epidermal Growth Factor Promotes Proliferation and Migration of Follicular Outer Root Sheath Cells via Wnt/β-Catenin Signaling Cell Physiol Biochem 2016;39:

Volume 135, Issue 3, Pages (September 2008)

SDHB deficiency promotes TGFβ-mediated invasion and metastasis of colorectal cancer through transcriptional repression complex SNAIL1-SMAD3/4 Haiyu Wang,

Volume 12, Issue 2, Pages (February 2013)

Volume 141, Issue 5, Pages e1 (November 2011)

Volume 137, Issue 4, Pages e3 (October 2009)

Volume 137, Issue 2, Pages (August 2009)

Intermittent cyclic mechanical tension promotes endplate cartilage degeneration via canonical Wnt signaling pathway and E-cadherin/β-catenin complex cross-talk

Victoria Sherwood, Irene M. Leigh Journal of Investigative Dermatology

Volume 18, Issue 12, Pages (December 2016)

Teruaki Fujishita, Masahiro Aoki, Makoto M. Taketo Gastroenterology

Volume 135, Issue 3, Pages (September 2008)

The Cancer Stem-Cell Hypothesis: Its Emerging Role in Lung Cancer Biology and Its Relevance for Future Therapy John D. O’Flaherty, MB, BCh, BAO, Martin.

Michèle Algarté-Génin, Olivier Cussenot, Pierre Costa European Urology

Wnt5a/β-Catenin Signaling Drives Calcium-Induced Differentiation of Human Primary Keratinocytes Tanja Popp, Dirk Steinritz, Andreas Breit, Janina Deppe,

BMP Receptor 1a and Juvenile Polyposis Syndrome

Volume 5, Issue 6, Pages (December 2013)

Uc.454 Inhibited Growth by Targeting Heat Shock Protein Family A Member 12B in Non- Small-Cell Lung Cancer Jun Zhou, Chenghai Wang, Weijuan Gong, Yandan.

The Ying and Yang of Bacterial Signaling in Necrotizing Enterocolitis

Volume 134, Issue 2, Pages e3 (February 2008)

MITF upregulation leads to Hsp90i resistance

Volume 23, Issue 10, Pages (October 2016)

Glucose-Induced β-Catenin Acetylation Enhances Wnt Signaling in Cancer

Volume 7, Issue 2, Pages (August 2016)

Inducible Nitric Oxide Synthase Up-Regulates Notch-1 in Mouse Cholangiocytes: Implications for Carcinogenesis Norihisa Ishimura, Steven F. Bronk, Gregory.

A Versatile Transcriptional Effector of Wingless Signaling

1 Oncomine database: DKK2 upregulation in colorectal cancers(CRC)

A and B, CO-1686–resistant NCI-H1975 cell clones, COR1-1 and COR10-1 display a reduced dependence on EGFR signaling for survival. A and B, CO-1686–resistant.

Long Noncoding RNA BC as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3 Jiaxin Lin, Xin Tan,

Knocking down Wnt3 increases the cells' response to trastuzumab and reduces cells' invasiveness. Knocking down Wnt3 increases the cells' response to trastuzumab.

Volume 119, Issue 4, Pages (October 2000)

Ectopic expression of caveolin-1 in ZR75 human breast cancer cells downregulated survivin and decreased cell proliferation. Ectopic expression of caveolin-1.

Another niche for Notch

Volume 4, Issue 4, Pages (April 2009)

and Other Unstable mRNAs

BCL-3 regulates expression of stemness-associated Wnt targets.

Identification of NSC as a FADD-kinase inhibitor.

Notch signaling from tumor cells: A new mechanism of angiogenesis

Competition between FLYWCH1/β-catenin and TCF4/β-catenin complexes for their interaction to Tcf-DNA-binding sites. Competition between FLYWCH1/β-catenin.

Sensor siRNAs can be used in high-order combinations.

Neoplasia lecture 7 Dr Heyam Awad FRCPath.

Western blot analysis of Wnt signaling genes.

Fig. 3. KMS99220 inhibits activation of NFκB signaling via HO-1 induction. (A) BV2 cells were treated with 10 µM KMS99220 for 1 h, and then treated with.

The critical roles of miR-23a and miR-27a in colorectal cancer progression. miR-23a primarily increases cell motility through downregulation of its target.

FGF19 amplification in liver cancer cell lines is associated with response to NVP-BGJ398. FGF19 amplification in liver cancer cell lines is associated.

Presentation transcript:

The interaction between the Wnt –and Notch-pathways in colorectal cancer development by: John Grünberg The aim is to study the interaction between the Wnt –and Notch-pathways with focus to see if the Wnt pathway regulates the Notch-pathway, and if this process is important for colorectal cancer development and/or progression. H0: There are no interactions between the Wnt –and the Notch pathways. H1: There is an interaction between Wnt-pathway and Notch-pathway.

Results APC/ β-catenin

Results DAPT treatment

Discussion  Downregulation of Cyclin D1 was expected – Proof of Wnt inhibition  Hes 1 downregulation – if Notch pathway was affected  Hes 7, JAG 2, MAML 1, Notch 2, NUMB, NUMBL, RFNG and LFNG was also downregulated.  All but JAG 2 contains one or more theoretical LEF1/TCF sites  JAG 1 and Notch1 are not downregulated  Notch 1 does not contain any theoretical LEF1/TCF sites - regulated in an alternative way  JAG 1 does contain 3 theoretical sites, upregulated in hairy follicles by β -catenin activation - JAG 1 may not be regulated by β -catenin in colon  Same genes as in HT29-APC are also downregulated in the trails with siRNA against β - catenin. Effects are due to decreased intracellular levels of β -catenin and hence an inhibition of the Tcf/Lef target gene program.  To confirm Notch is inhibited – western blot analysis against Hes 1 protein  Western blot against β -catenin showed that the intracellular levels was not affected  Confirmed by a semi quantitative PCR:  β -catenin target gene Cyclin D1 had a homogenous expression in all treatment, but Hes 1 was downregulated  These preliminary results indicate: no regulation of APC/ β -catenin by the Notch pathway.  However, further studies are warranted to elucidate the mechanism fully.

Conclusion  By inhibiting the Wnt pathway, our results have shown downregulation of:  one ligand (JAG 2)  one receptors (Notch 2)  one transcriptional activator (MAML 1)  two target genes (Hes 1, Hes 7)  two inhibitors (NUMB, NUMBL)  two of Notch glycosyltransferases (LFNG, RFNG)  Is accomplished by the Tcf/Lef target gene program, shown by transfecting the cells with siRNA against β -catenin.  This total down regulation of the Notch pathway upon Wnt deactivation shows a correlation between the two signaling pathways in colorectal cancer. We did not find any correlation the other way around, between Notch inhibition and Wnt pathway through β -catenin signalling.  Using gamma-secretase inhibitors may provide a targeted-drug strategy for treating human colorectal cancer, because of the close correlation between the Notch and Wnt pathway  Inhibition of Notch signalling gives a decrease in Hes 1 gene expression, leading to halt of cell proliferation and generation of apoptosis  Preclinical studies for Alzheimer’s disease in rodents have shown that a side effect of gamma-secretase inhibitors is macroscopic abnormalities in the GI-tract, where the small and large intestine is distended and with an excess of mucus  This may be one way of inhibiting the upregulation of the Notch pathway in colorectal cancer.