ASSISTANT PROFESSOR, BIOCHEMISTRY AND MOLECULAR BIOLOGY
Phone: 402-559-3177 (Office)
M.D., Saint Louis University, St. Louis, Missouri 2004
Ph.D., Saint Louis University, St. Louis, Missouri 2003
Research Opportunities in my laboratory:
Graduate students considered on an individual basis
Medical students, summer research
Cholangiocarcinoma (liver cancer)
MicroRNA expression and function
Apoptosis resistance mechanisms
Cholangiocarcinoma cell death mechanisms
My lab is focused on cell death in liver cancer, specifically cholangiocarcinoma, a malignant tumor arising in the bile duct epithelium. Clinically, this tumor is very difficult to treat and the prognosis is very poor. In part, this is due to resistance of tumor cells to apoptosis upon chemotherapy or targeted therapy. Cholangiocarcinoma cells resist apoptotic signaling induced by TRAIL (a tumor surveillance death ligand), both through elevated Mcl-1 protein levels and through attenuated death receptor signaling. Decreased apoptosis signaling may impact the response to anti-tumor therapies, and reversing this resistance has the potential to improve treatment of this devastating disease.
I have established a distinct line of investigation into dysregulation of microRNAs in cancer and the effects on cell death signaling. MicroRNA levels are commonly altered in cancer, and these changes have the potential to affect hundreds of gene targets and significantly influence cell function. For instance, we discovered that Mcl-1 protein levels are decreased by microRNA-mediated silencing, and specifically that miR-29b targets Mcl-1 in cholangiocytes. This regulation is lost in malignant cells which have lower levels of miR-29b. Increasing the cellular miR-29b levels rendered malignant cells sensitive to TRAIL killing.
Additional pathways whereby microRNAs regulate apoptosis are being pursued. Interestingly, in addition to targeting the survival protein Mcl-1, miR-29b is also predicted to target additional Bcl-2 family members. Does miR-29b play a broader role in apoptotic signaling by refining expression at multiple points in the pathway?
Additionally, we have data implicating the oncogenic mir-106b~25 cluster in regulating TRAIL death receptor signaling. Promising data to date illustrate that miR-25 is antiapoptotic by way of targeting DR4 and antagonism of miR-25 promotes cholangiocarcinoma cell death.
Selected Recent Publications
Gupta S, Read DE, Deepti A, Cawley K, Gupta A, Oomen D, Verfaillie T, Matus S, Smith MA, Mott JL, Agostinis P, Hetz C, and Samali A. (2012) Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. Cell Death and Disease 3, e333; doi: 10.1038; in press. PMID: 22739985
Razumilava N, Bronk SF, Smoot RL, Fingas CD, Werneburg NW, Roberts LR, Mott JL. (2012) miR-25 targets TRAIL death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma. Hepatology, 55(2):465-475. PMID: 21953056 [*Corresponding author].
Fingas CD, Bronk SF, Werneburg NW, Mott JL, Guicciardi ME, Cazanave SC, Mertens JC, Sirica AE, Gores GJ. (2011) Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology, 54(6):2076-88. PMID: 22038837
Cazanave SC, Mott JL, Elmi NA, Bronk SF, Masuoka HC, Charlton MR, Gorres GJ. (2011) A role for miR-296 in the regulation of lipoapoptosis by targeting PUMA. Journal of Lipid Research, 52(8):1517-25. PMID: 21633093
Kurita S, Mott JL, Cazanave SC, Fingas CD, Guicciardi ME, Bronk SF, Roberts LR, Fernandez-Zapico ME, Gores GJ. (2011) Hedgehog inhibition promotes a switch from type II to type I cell death receptor signaling in cancer cells. PLoS ONE, 6(3):e18330. PMID: 21483830
Guicciardi ME, Mott JL, Bronk SF, Kurati S, Fingas CD, Gores GJ. (2011) Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Experimental Cell Research, 317(1):107-16. PMID: 20951133.
Kurta S, Mott JL, Almada LL, Bronk SF, Werneburg NW, Sun S-Y, Fernandez-Zapico ME, Gores GJ. (2010) GLI3-Dependent repression of DR4 mediates hedgehog antagonism of TRAIL-induced apoptosis. Oncogene, 29(34):4848-58. PMID: 20562908
Fingas CD, Blechacz BA, Smoot RL, Guicciardi ME, Mott J, Bronk SF, Werneburg NW, Sirica AE, Gores GJ. (2010) A Smac mimetic reduces TRAIL-induced invasion and metastasis of cholangiocarcinoma cells. Hepatology, 52(2):550-61. PMID: 20683954
Mott JL*, Kurita S, Cazanava SC, Bronk SF, Werneburg NW, Fernandez-Zapico ME. (2010) Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, Hedgehog and Nf-kappaB. Journal of Cellular Biochemistry, 110(5):1155-64. PMID: 20564213 [*corresponding author]
Steele R, Mott JL, Ray RB. (2010) MBP-1 upregulates miR-29b that represses Mcl-1, collagens, and matrix metalloproteinase-2 in prostate cancer cells. Genes & Cancer, 1(4):381-387. PMID: 20657750
Mott JL. (2009) MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia. (Invited review) Hepatology, 50(2):630-7. PMID: 19585622
Mott JL, Kobayashi S, Bronk SF, Gores GJ. (2007) mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26(42):6133-40. PMID: 17404574
Research Grants Awarded
Apoptosis Effectors Targeted by Hedgehog-Supported MicroRNAs
8/1/2011 - 6/30/2013
Goal: This proposal will investigate the mechanisms by which Hedgehog signaling controls expression of the microRNA cluster, mir-106b~mir-25. In addition, the mechanisms by which miR-106b, miR-93, and miR-25 repress apoptosis-related targets will be explored.
Cholangiocyte microRNAs Regulate Mcl-1 and Cell Death
9/12/2007 - 8/31/2012
Goals: This career development award is designed to support the PI as a junior investigator of the mechanisms of dysregulated expression of mir-29b in cholangiocarcinoma and how this results in overexpression of Mcl-1, rendering this cancer apoptosis-resistant.
Surinder K. Batra
William G. Chaney
G. Stanley Cox
Richard G. MacDonald
Parmender P. Mehta
Robert F. Ramaley