Colorectal cancer is the third most common cancer in the US, with approximately 145,000 new cases expected in 2005. Estimated 5-year survival rates range from 90% for patients with early diagnosis (stage I disease) and fall to <10% for patients with metastatic colorectal cancer (CRC). In this renewal application, we move to studies of the role of Reg IV in the development of mucosal cancers. Studies during the current funding period, presented as the foundation for this application, have demonstrated that: i) Expression of Reg IV is increased in adenomatous polyps and in CRCs, often to very high levels, ii) Increased expression Reg IV is one of the earliest steps in the formation of tumors, coinciding with the second spontaneous mutation in the APC gene and adenomatous change by histology in APCmin/+mice, iii) Reg IV is a potent activator of a signaling pathway (the EGFR-Akt-AP1) in CRC and leads to increased expression of Bcl-2, Bcl-XL, survivin and matrilysin. These genes have all previously been associated with a poor prognosis in advanced CRC, iv) Treatment of CRC cells with recombinant Reg IV protein significantly reduces their susceptibility to death by programed cell death (apoptosis), following radiation or chemotherapeutic drugs, and v) Function blocking anti-Reg IV mAbs or interfering RNAs have potent antagonistic effects on cell growth and increase susceptibility to apoptotic death following radiation or administration of chemotherapeutic drugs. By utilizing the approaches, outlined in the proposal, our goal is to better understand the mechanisms involved in the clinical resistance of CRC to conventional therapy and to ascertain the role of Reg IV as a cause of poor outcome. These studies will also provide new insight into the role of Reg IV antagonists and lay the groundwork for development of therapeutic reagents active in gastrointestinal adenocarcinomas.

Public Health Relevance

Colorectal cancer is the third most common cause of cancer and the second leading cause of cancer death. We identified a novel protein, Reg IV, which is an important regulator of tumor cell growth, invasion and resistance to treatment. These studies will provide critical insight into the potential role of Reg IV antagonists as a new treatment for gastrointestinal cancers.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Hamilton, Frank A
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Bishnupuri, Kumar S; Sainathan, Satheesh K; Bishnupuri, Kislay et al. (2014) Reg4-induced mitogenesis involves Akt-GSK3β-β-Catenin-TCF-4 signaling in human colorectal cancer. Mol Carcinog 53 Suppl 1:E169-80
Kerr, T A; Ciorba, M A; Matsumoto, H et al. (2012) Dextran sodium sulfate inhibition of real-time polymerase chain reaction amplification: a poly-A purification solution. Inflamm Bowel Dis 18:344-8
Sainathan, Satheesh K; Bishnupuri, Kumar S; Aden, Konrad et al. (2012) Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis. Inflamm Bowel Dis 18:955-67
Bishnupuri, Kumar S; Luo, Qizhi; Sainathan, Satheesh K et al. (2010) Reg IV regulates normal intestinal and colorectal cancer cell susceptibility to radiation-induced apoptosis. Gastroenterology 138:616-26, 626.e1-2
Csillag, Claudio; Nielsen, Ole Haagen; Vainer, Ben et al. (2007) Expression of the genes dual oxidase 2, lipocalin 2 and regenerating islet-derived 1 alpha in Crohn's disease. Scand J Gastroenterol 42:454-63
Bluth, Martin H; Patel, Sameer A; Dieckgraefe, Brian K et al. (2006) Pancreatic regenerating protein (reg I) and reg I receptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis. World J Gastroenterol 12:4511-6
Bishnupuri, Kumar S; Luo, Qizhi; Murmu, Nabendu et al. (2006) Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas. Gastroenterology 130:137-49
Ahuja, Vineet; Dieckgraefe, Brian K; Anant, Shrikant (2006) Molecular biology of the small intestine. Curr Opin Gastroenterol 22:90-4
Bishnupuri, Kumar S; Luo, Qizhi; Korzenik, Joshua R et al. (2006) Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes. Cancer Biol Ther 5:1714-20
Mukhopadhyay, Debnath; Houchen, Courtney W; Kennedy, Susan et al. (2003) Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2. Mol Cell 11:113-26

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