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Loyola Medicine, Department of Medicine Stritch School of Medicine Stained Glass Window
Research
Gastroenterology, Hepatology & Nutrition

Overview
The overall mission of the research activities in the Division is to conduct original scientific investigations in diseases and disorders of the digestive system, including the gastrointestinal (GI) tract, liver and pancreas. Research within the division can be broadly divided into basic science research and clinical investigation. The areas of interest include:

Faculty Specific Research Interests:

Claus Fimmel, MD
Lorinda Wright, PhD
We are interested in liver disease, and in particular hepatocellular cancer. We have previously identified a resident Golgi membrane protein known as GP73 which becomes upregulated in hepatocytes during liver disease, and is much more highly upregulated in hepatocellular carcinoma (HCC) [1, 2]. Furthermore, the long C-terminus of this protein appears in the serum of HCC patients, making GP73 an attractive candidate for a serum marker for the early detection of HCC [3]. Our work has focused on understanding the normal function of GP73, which at present is unknown, as well as its role in HCC.
We have developed a line of transgenic mice which express a severely truncated form of GP73. These mice have a much lower cumulative survival rate compared to wild-type mice, and spontaneously develop hepatic abnormalities including steatosis and nuclear atypia, which is a common feature of cancer. GP73-truncated mice also develop renal pathologies including glomerulosclerosis and the accumulation of hyaline thrombi [4].

In addition to these spontaneous abnormalities, GP73-truncated mice have proven to be dramatically more susceptible to chemically-induced hepatocellular cancer, suggesting that GP73 may be a tumor-suppressor. Furthermore, intriguing gender-related differences in tumor susceptibility have suggested that GP73 may be hormonally regulated, and may play a greater tumor-suppressor role in females.

Ongoing work in our lab is focusing on the elucidation of the molecular and biochemical mechanisms of increased carcinogenesis in GP73-truncated mice, and thus the specific cellular functions of GP73. We hope this work will lead to improved diagnostic tools for HCC, and a better understanding of the mechanisms of hepatic and renal pathologies.

Literature Cited:

  1. Marrero JA, Romano PR, Nikolaeva O, Steel L, Mehta A, Fimmel CJ, Comunale MA, et al. GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma. J. Hepatol. 2005;43:1007-1012.
  2. Block TM, Comunale MA, Lowman M, Steel LF, Romano PR, Fimmel C, Tennant BC, et al. Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans. Proc. Natl. Acad. Sci. U.S.A. 2005;102:779-784.
  3. Bachert C, Fimmel C, Linstedt AD. Endosomal trafficking and proprotein convertase cleavage of cis Golgi protein GP73 produces marker for hepatocellular carcinoma. Traffic 2007;8:1415-1423.
  4. Wright LM, Yong S, Picken M, Rockey D, Fimmel C. Decreased survival and hepato-renal pathology in mice with C-terminally truncated GP73 (GOLPH2). Submitted to Int. J. Exp. Path. 2008.

Sharad Khare, PhD
Environmental factors, including dietary fats, are implicated in colonic carcinogenesis. Dietary fats modulate secondary bile acids including deoxycholic acid (DCA) concentrations in the colon, which are thought to contribute to the nutritional-related component of colon cancer risk. Research in my laboratory focuses on the regulation of cyclooxygenase-2 (Cox-2) gene expression by bile acids. Our laboratory has previously found that deoxycholic acid (DCA) promotes colonic carcinogenesis in the azoxymethane (AOM) model of colon cancer. In contrast, another bile acid, ursodeoxycholic acid (UDCA), inhibits AOM tumor incidence. Recently, we have found that tumor inhibiting UDCA also reverses the AOM-induced increase in Cox-2 expression. This inhibition of AOM-induced Cox-2 by UDCA, therefore, most likely contributes to the chemopreventive actions of UDCA in this model. More recently, we have employed a cell culture model to dissect the molecular mechanisms involved in Cox-2 regulation. In this system, Cox-2 is strongly induced by tumor-promoting DCA and this induction is inhibited by tumor-preventing UDCA. This cell culture model will, therefore, allow us to elucidate the cis- and trans-acting elements that mediate Cox-2 suppression by UDCA.

In addition, we use the AOM model to study aberrant crypt foci (ACF) that develop in the premalignant phase in rats, as well as in humans. We have found several epigenetic alterations in ACF, examples of which include increased cyclin D1 and Cox-2 expression. The AOM model of colon cancer provides an ideal opportunity to identify causal premalignant events and characterize their time course. This phase extends up to 18 weeks following carcinogen treatment prior to development of overt tumors. Similar studies in man are not possible. Changes in the premalignant (ACF) stage, which persist or are accentuated in the malignant phase of this model, will identify potential biomarkers for screening human colon cancer. Chemopreventive UDCA significantly suppresses ACF in AOM model. We are evaluating the mechanisms by which the progression of normal epithelial cells to ACF can be prevented.

A third focus of our laboratory is to study the regulation of Focal Adhesion Kinase (FAK) by tumor promoting DCA. We have demonstrated, for the first time that DCA differentially regulates the site-specific phosphorylation of FAK and provided a possible mechanism for inside-out signaling by DCA in colon cancer cells. Our results define a new signaling pathway, originating with DCA-induced FAK dephosphorylation. Our results suggest that DCA differentially regulates signaling from focal adhesion complexes through selective phosphorylation and dephosphorylation or through association of participating components. These regulatory events may have distinct roles in diverse physiological and disease processes including inflammation, wound healing, and cancer progression.

Literature Cited:

  1. Sonia R. Cerda, Reba Mustafi, Holly Little, Greg Cohen, Christopher Moore, Sharad Khare, and Marc Bissonnette (2006) Protein Kinase C Delta Inhibits Cell Proliferation in CaCo-2 Cells by Selective Cell Cycle and Cell Death Regulators. Oncogene, 25, 3123-3138.
  2. Greg Cohen, Nathaniel Little, Reba Mustafi, Piotr Obara, Loren Joseph, John Hart, Lisa Yerian, Maria Tretiakova, Sharad Khare, Frank A. Sinicrope, Alessandro Fichera, Gerry R. Boss, Robert Carroll and Marc Bissonnette (2006) Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci. Cancer Research, 66: 5456-5464.
  3. harad Khare, Cory Holgren, and Allen M. Samarel (2006) Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: Role of tyrosine phosphatase ShP2. Am J Physiol Gastrointest Liver Physiol. 291(6): G1100-12.
  4. Alessandro Fichera, Nathaniel Little, Sonia Cerda, Sujatha Jagadeeswaran, Sharad Khare, Maria Tretiakova, Can Gong, Greg Cohen, Loren Joseph, John Hart, Jerry Turner and Marc Bissonnette (2007) Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis. Cancer Research 67(2): 827-35.
  5. Sharad Khare, Reba Mustafi, Greg Cohen, Sonia Cerda, Cory Holgren, Ramesh Wali, Christopher Moore and Cory Holgren, Allen Samarel and Marc Bissonnette (2008). Ursodeoxycholic Acid Suppresses Cox-2 Expression in Colon Cancer: Roles of Ras, p38 and CCAAT/Enhancer-Binding Protein. Nutrition and Cancer. Accepted.
  6. Sharad Khare, Kamran Chaudhury, Marc Bissonnette, and Robert Carroll (2008) Aberrant Crypt Foci in Colon Cancer Epidemiology. Cancer Epidemiology (Book Chapter, In Press).

Basabi Rana, PhD
Research in my laboratory focuses on identifying both the positive and negative regulators of growth. In one of the projects and to identify the positive regulators of growth, we have initiated studies at a molecular level to understand the mechanism(s) underlying the trophic effects of the gastrointestinal peptide hormone (gastrin) in cancer cells. These studies identified the oncoprotein beta-catenin and the transcription factor CREB as candidate upstream mediators of gastrin induced growth, involving the cell cycle regulator protein cyclin D1 [1]. Studies are currently underway to determine specifically the role of these molecules in cancer cell proliferation and migration and to identify the upstream signaling pathways involved. These studies are expected to provide a mechanistic insight into the mechanism and identify specific signaling pathways responsible for mediating the trophic effects of gastrin. My future goal with these studies is to determine whether a similar mechanism operates in an in vivo environment.

In a second project and to identify the negative regulators of growth, we have focused on the transcription factor Peroxisome Proliferator Activated Receptor (PPAR) gamma. Ligand mediated activation of PPARgamma has been shown to be effective in regulating growth in multiple cancer cells. Our earlier studies revealed that Troglitazone mediated activation of PPARgamma can inhibit growth of the liver cells [2]. Active research is currently underway in my laboratory to determine the role of Troglitazone and other PPARgamma ligands in regulating survival and apoptotic pathways in gastrointestinal cancer cells. Earlier studies from my laboratory also revealed some novel pathways of beta-catenin degradation following activation of PPARgamma [3]. We are now extending these studies to identify the key mediators involved in this pathway of beta catenin degradation. Since beta catenin is mutated or overexpressed in many cancer types, this novel degradation pathway might be effective in regulating these resistant tumors via regulating mutated beta catenin expression.

In a separate project, we are carrying out studies to identify the specific signaling pathways operating in the cancer cells to regulate the expression levels and signaling via beta catenin. This has the potential of opening new possibilities of developing targeted cancer therapies for treating beta catenin dependent resistant tumors. In pilot studies our laboratory recently identified a cross-talk of a Stress Kinase family member in regulating beta catenin pathway in prostate cancer.

Literature Cited:

  1. Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming JV, Wang TC, Wolfe MM, Baker KM, Pestell RG, Rana B: Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene 2004, 23:3689-3699.
  2. Sharma C, Pradeep A, Pestell RG, Rana B: Peroxisome proliferator-activated receptor gamma activation modulates cyclin D1 transcription via beta-catenin-independent and cAMP-response element-binding protein-dependent pathways in mouse hepatocytes. J Biol Chem 2004, 279:16927-16938.
  3. Sharma C, Pradeep A, Wong L, Rana A, Rana B: Peroxisome proliferator-activated receptor gamma activation can regulate beta-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway. J Biol Chem 2004, 279:35583-35594.

Clinical Science Research Areas of Interest
Pancreatitis

Principal Investigators
John Affronti