Central Drug Research Institute, Lucknow, India 1993
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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 allowing for epithelial-to-mesenchymal transition (EMT) to occur. Whether these changes further promote metastasis and/or frank malignancy is currently being investigated.
Roy BC, Subramaniam D, Ahmed I, Jala VR, Hester C, Greiner AK, Haribabu B, Anant S, Umar S. (2014) Role of bacterial infection in the epigenetic regulation of Wnt antagonist WIF1 by PRC2 protein EZH2. Oncogene (Revision under review)
Chandrakesan P, Weygant N, May R, Qu D, Chinthalapally HR, Sureban SM, Ali N, Lightfoot SA, Umar S, Houchen CW. (2014) DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition. Oncotarget, Sep 2. [Epub ahead of print] PMID: 25211188.
Greiner AK, Papineni RV, Umar S. Natural Products and Microbiome. (2014) Am. J. Physiol. Gastrointest. Liver Physiol. 307: G1-G15.
Chandrakesan P, Roy B, Jakkula LU, Ahmed I, Ramamoorthy P, Tawfik O, Papineni R, Houchen C, Anant S, Umar S. (2014) Utility of a bacterial infection model to study epithelial-mesenchymal transition, mesenchymal-epithelial transition or tumorigenesis. Oncogene 33, 2639-2654.
Chandrakesan P, Jakkula LUMR, Ahmed I, Roy B, Anant S and Umar S. (2013) Differential effects of b-catenin and NF-kB interplay in the regulation of cell proliferation, inflammation and tumorigenesis in response to bacterial infection. PLOS ONE 8: e79432.
Ahmed I, Roy B, Chandrakesan P, Venugopal A, Xia L, Jensen R, Anant S, Umar S. (2013) Evidence of functional cross talk between the Notch and NF-kB pathways in nonneoplastic hyperproliferating colonic epithelium. Am J Physiol Gastrointest Liver Physiol. 304: G356-370.
Ahmed I, Chandrakesan P, Tawfik O, Xia L, Anant S and Umar S. (2012) Critical roles of Notch and Wnt/b-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection. Infection and Immunity 80: 3107-3121.
Chandrakesan P, Ahmed I, Chinthalapally A, Singh P, Awasthi S, Anant S and Umar S. (2012) Distinct compartmentalization of Nuclear Factor-kB activity in the crypt and crypt-denuded lamina propria precede and accompany hyperplasia and/or colitis following bacterial infection. Infection and Immunity 80: 753-767.
Chandrakesan P, Ahmed I, Wang Y, Sarkar S, Singh P, Peleg S, and Umar S. (2010) Novel changes in NF-kB activity during progression and regression phases of hyperplasia: Role of ERK1/2 and p38. J. Biol. Chem. 285: 33485-98.
Sellin JH, Wang Y, Singh P, Umar S. (2009) b-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia. Exp. Cell Res. 315: 97-109.
Umar S, Sarkar S, Wang Y, and Singh P. (2009) Functional cross-talk between b-catenin and NF-kB signaling pathways in colonic crypts of mice in response to Progastrin. J. Biol. Chem. 284: 22274-22284.
Umar S, Sarkar S, Cowey S, Singh P. (2008) Activation of NF-kB is required for mediating proliferative and anti-apoptotic effects of progastrin on proximal colonic crypts of mice, in vivo. Oncogene 27, 5599-5611.
Rengifo-Cam W, Umar S, Sarkar S, Singh P. (2007) Anti-apoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of NF-kB. Cancer Res. 67: 7266-74.
Umar S, Wang Y, Sellin JH. (2005). Epithelial proliferation induces novel changes in APC expression. Oncogene 24: 6709-6718.
Shahid Umar, Ph.D.
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