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/-catenin and Notch and NF-B 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-B 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 transdifferentiation 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/-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.
Chandrakesan P, Ahmed I, Singh P, Awasthi S, Anant S and Umar S. (2011) Distinct compartmentalization of Nuclear Factor-B activity in the crypt and crypt-denuded lamina propria precede and accompany hyperplasia and/or colitis following bacterial infection. Infection and Immunity (In press).
Subramaniam D, Nicholes ND, Dhar A, Umar S, Awasthi V, Welch DR, Jensen RA, Anant S. (2011) 3,5-bis (2,4-difluorobenzylidene)-4-piperidone, a novel compound that affects pancreatic cancer growth and angiogenesis. Mol. Cancer Therapeutics. Oct 18. [Epub ahead of print].
Ali N, Allam H, May R, Sureban SM, Bronze MS, Bader T, Umar S, Anant S. and Houchen CW. (2011) Hepatitis C Virus-Induced Cancer Stem Cell-like Signatures in Cell Culture and Murine Tumor Xenografts. J. Virology. Sep 21. [Epub ahead of print].
He Z, Subramaniam D, Ramalingam S, Dhar A, Postier R, Umar S, Zhang Y and Anant S. (2011) combination with honokiol enhances killing of human colorectal cancer cells by radiation: enhanced activity in cells with mismatch repair defects. Am. J. Physiol. 301: G929-G937.
Ahmed I, Chandrakesan P, Xia L, Anant S and Umar S. (2011) Critical roles of Notch and Wnt/-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection. Infection and Immunity (under review).
Umar, S. (2010) Intestinal Stem Cells. Curr. Gastroenterology Rep. 12: 340-348.
Chandrakesan P, Ahmed I, Wang Y, Sarkar S, Singh P, Peleg S, and Umar S. (2010) Novel changes in NF-B activity during progression and regression phases of hyperplasia: Role of ERK1/2 and p38. J. Biol. Chem. 285: 33485-98.
Peleg S, Sellin JH, Wang Y, Freeman MR, and Umar S. (2010) Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium. Am. J. Physiol. 299: G593-601.
Singh P., Sarkar, S., Umar S., Rengifo-Cam W., Singh AP, Wood TG. (2010) Insulin-like growth factors are more effective than progastrin in reversing proapoptotic effects of curcumin: critical role of p38MAPK. Am J Physiol. 298: G551-G562.
Sellin JH, Wang Y, Singh P, Umar S. (2009) -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 -catenin and NF-B 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-B 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-B. Cancer Res. 67: 7266-74.
Umar S, Wang Y, Morris AP, Sellin JH. (2007) Dual alterations in casein kinase 1 and GSK-3 modulate -catenin stability in hyperproliferating colonic epithelia. Am. J. Physiol. 292: G599-G607.
Wang Y, Kourouma F, Guang-Sheng X, Umar S. (2006) Citrobacter rodentium-induced NF-B activation in hyperproliferating colonic epithelia: role of p65 (Ser536) phosphorylation. British Journal of Pharmacology, 148:814-824.
Umar S, Wang Y, Sellin JH. (2005). Epithelial proliferation induces novel changes in APC expression. Oncogene 24: 6709-6718.