Role of the Cholecystokinin-B Receptor in Proliferation of Pancreatic Cancer

Open Access
- Author:
- Fino, Kristin Kelly
- Graduate Program:
- Cell and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 09, 2012
- Committee Members:
- Jill P Smith, Dissertation Advisor/Co-Advisor
Dr Mark Kester, Committee Chair/Co-Chair
Rosalyn Bryson Irby, Committee Member
Lisa M Shantz, Committee Member
Hong Gang Wang, Special Member - Keywords:
- pancreatic cancer
gastrin
CCK-BR
G-protein coupled receptor
RNAi - Abstract:
- Pancreatic cancer ranks as the fourth most common cause of cancer-related mortality with a five-year survival rate of less than 1% and a median survival of 3-6 months. Although numerous chemotherapeutic drugs have been tested in this malignancy, survival of advanced pancreatic cancer has not improved over the past several decades. Unlike other cancers, which have markers for early detection, current pancreatic cancer predictive indicators lack sensitivity and specificity. Due to the lack of effective treatment and early screening options available for this disease, identification of novel targets and approaches are desperately needed. The human cholecystokinin-B receptor (CCK-BR) and its ligand, gastrin, are up-regulated in pancreatic cancer compared to normal tissues. Growth of pancreatic cancer is controlled by the interaction of gastrin with the CCK-BR through an autocrine and exocrine mechanism. The CCK-BR may be a promising therapeutic target. One of the goals of this study was to characterize the role of the CCK-BR in human pancreatic cancer proliferation, apoptosis, and migration. Down-regulation of the CCK-BR by RNA interference (RNAi) resulted in reduced cancer cell proliferation and an increase in apoptotic activity evidenced by increased caspase-3 activity, TUNEL positive cells, and decreased XIAP expression. In addition, cancer cell mobility was also decreased upon CCK-BR down-regulation. An alternatively spliced isoform of the CCK-BR, the CCK-CR, retains intron 4 which is expressed as an extra 69 amino acids in the 3rd intracellular loop. Unlike the CCK-BR, this splice variant is expressed only in malignant tissues. The second goal of this study was to evaluate the CCK-CR as a diagnostic tool for detection of pancreatic cancer. Detection of CCK-CR mRNA was problematic due to low transcript abundance and the sequence similarity to the CCK-BR. CCK-CR detection proved more reliable and consistent at the protein level. The CCK-BR holds promise as a potential therapeutic target, as strategies to decrease the CCK-BR expression and activity may be beneficial for development of new treatments. Also detection of the CCK-CR could aid in development of screening options for pancreatic cancer. The data presented in this thesis give further support for both of these hypotheses.