Projects
Molecular study of Axin in normal and cancer cells
Axins (Axin1 and Axin2) are negative regulator of the Wnt signaling pathway as their over-expression results in beta-catenin down-regulation. Axin is able to bring beta-catenin and GSK3s into close proximity, thus facilitating beta-catenin phosphorylation. A variety of in vitro and in vivo studies, suggest that Axin serves as a scaffold protein that binds directly many proteins involved in Wnt signaling pathway. Axin contains several domains that mediate direct binding to APC, GSK3s (GSK3a and GSK3b), beta-catenin, Dishevelled, PP2A, CK1, MEEK1, as well as Axin itself. Deregulation of both Axin1 and Axin2 have been found in different forms of cancer (Sima Salahshor and James R Woodgett). The aim of this project is to explore how Axin deregulation contributes to carcinogenesis.
Identification and characterization of novel Axin-interacting partners
One of the most reliable approaches for determining the novel function of a given protein is to see if it is interacting with another protein with a known function.
Our approach is based on isolating Axin protein assemblies and characterising the components by mass spectrometry (MS). We are also exploring how distruption in these novel Axin-protein complexes lead to human diseases.
Biomarker discovery for early detection of colorectal cancer
Identification of gene products whose abnormal expression can be detected at early stage of tumor progression could improve the therapeutic index for tumor therapy.
Using cDNA microarrays comprising 19,200 human genes (www.microarrays.ca), we have examined the gene expression profile of adenomas and corresponding normal tissues obtained from patients with familial adenomatous polyposis (FAP). Statistical analysis using SAM and GeneTraffic revealed eighty four transcripts to be represented at statistically significant different levels in all adenomas compared to normal tissues (p< 0.05). Pregnancy specific beta-1 glycoprotein 9 (PSG9) was the most statistically significant candidate in these experiments and therefore was selected for further analysis (Sima Salahshor et al, 2005). This project was originally conducted in collaboration with scientists at Princess Margaret Hospital (PMH) and Mount Sinai Hospital (MSH).
Detailed molecular study of PSG9, as well as other identified tumor markers will help u
s to develop more accurate method(s) to detect, diagnose, and monitor cancer.
The abnormal expression of the other identified colorectal cancer biomarkers have also been verified in a series of primary tumors. Interestingly, abnormal expression of some of these early markers can also be detected in tumor metastasis.
Abnormal Wnt signaling in pancreas and esophageal cancerIn addition to colorectal cancer, we are investigating whether/how defect(s) in Wnt signal transduction contributes to pancreas and esophageal cancer initiation and/or progression.
After pancreas cancer, esophageal cancer is the most fatal type of cancer. So far very few genetics abnormalies have been directly linked to this type of disease. Recently, in collaboration with scientists at the Nelson Mandela School of Medicine in South Africa, Ontario Cancer Institute (OCI)/Princess Margaret Hospital (PMH) and the Samuel Lunenfeld Research Institute (SLRI)/ Mount Sinai Hospital (MSH) in Canada, we have shown that many components of the Wnt signal transduction pathway are deregulated in esophageal squamous cell carcinomas. In addition, we have been able to identify a specific type of E-cadherin abnormality that occurs more frequently in esophageal tumors (Sima Salahshor et al, 2008).
E-cadherin plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Loss of E-cadherin is believed to be an early step in metastatic dissemination. In esophageal cancer, the liver, lung and the bones are the most common sites of metastases. Metastasis is responsible for 90% of the deaths caused by cancer. The results of this study will increase our understanding of what triggers cancer cells to start the complicated process of metastasis, and hopefully will result in the generation of novel targets for therapies to aid in the prevention of metastasis.
