Central Drug Research Institute, Lucknow, India 1993
Research in my laboratory is focused on the role of bacterial infection in colonic crypt hyperplasia and/or inflammation and 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.
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.
In my lab, we also study how bacterial infection affects colonic stemness and trans-differentiation of colonic epithelial cells and whether these changes facilitate mucosal priming for neoplasia. Finally, my laboratory is also very actively involved in chemoprevention. Our model provides an excellent opportunity to study the effect of dietary intervention on complex interplay between the Notch and Wnt/b-catenin pathways before they become constitutive. We are currently investigating the mechanisms by which various signaling pathways affect mucosal priming for neoplasia and whether targeting these pathways may help ameliorate colitis or cancer.
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.
4028 Wahl Hall East
3901 Rainbow Blvd.
Kansas City, KS 66160
F: (913) 588-7430