Shahid Umar, PhD
Professor of Surgery
Vice Chair of Research
Research in my laboratory is focused on the role of bacterial infection in colonic crypt hyperplasia and/or inflammation and/or cancer. Specific research areas include: (a) Regulation of cross-talk between components of the Wnt/b-catenin and Notch and NF-kB and Notch pathways in relation to complex inter-relationship amongst cell proliferation, inflammation and cancer; (b) Cancer Stem Cells, and (c) mechanism(s) of chemoprevention by dietary factors and its novel derivatives.
The bacteria or microbiota present on the mucosal lining of our GI tract perform critical functions needed for proper metabolism and immune surveillance. For example, bacteria ferment undigested carbohydrates into short-chain fatty acids (SCFAs) that function as an energy source and control epithelial cell growth and differentiation. However, alterations in the microbiome, through changes such as infection or diet, can disturb this symbiotic relationship and promote cancer.
Notch signaling plays a critical role in maintaining progenitor/stem cell population as well as a balance between cell proliferation, differentiation and apoptosis. Upregulation of Notch signaling is also reported during inflammatory bowel disease (IBD). The Wnt signaling pathway also plays a crucial role during development of tissues and organisms. Wnt signaling cascades cross-talk with Notch signaling pathways to constitute the stem cell signaling network. Dysregulation of this network due to epigenetic and genetic alterations may lead to congenital abnormality and carcinogenesis.
What is less clear however is how the cross-talk between the two pathways is regulated in native epithelia and whether the pathogenic insult affects the cross-talk itself to trigger the disease process. Increased rates of proliferation form the earliest and most probably, the necessary background for the transformation of a normal colonic epithelium to cancer. A direct link between inflammation and cancer has also been established with NF-kB emerging as a key player. Recently, dysregulation of microRNAs has been observed in patients with ulcerative colitis. However, little is known about the functional consequence of dysregulation of miRNAs during chronic colitis in epithelial cells, and even less on tumorigenesis. We utilize an in vivo model of bacterial infection-induced hyperplasia of colonic crypts to study these complex pathways in real-time.
Using a Citrobacter rodentium model of bacterial infection, my lab has shown that Citrobacter can promote colon crypt hyperplasia and tumorigenesis by aberrantly regulating Wnt/β-catenin and Notch signaling pathways (Figure 1). We have further demonstrated that Citrobacter causes elevated expression of the histone methyltransferase EZH2 in infected colon crypts and tumors. EZH2 catalyzes transcriptional repression of E-cadherin to promote epithelial-mesenchymal-transition (EMT) to occur. Whether these changes further promote metastasis and/or frank malignancy is currently being investigated.
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