Medical Student Research Fellowship for Summer 2003

Mentor: Rhonda F. Souza M.D.
Department: Medicine/Gastroenterology
Room number: VA bldg 43 room 120
Mail Code: 111B1
Phone number:214 857-0301
E-mail: rsouza@airmail.net
Project title: Loss of imprinting as a mechanism for IGFII overexpression in Barrett's esophagus

Human subjects IRB approved project number (where applicable):VA 99-042

Animal subjects IRB approved project number (where applicable):

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project: Patient-based research
Gastroesophageal reflux disease (GERD) has been established as a strong risk factor for adenocarcinoma of the esophagus. In some individuals, the chronic esophageal inflammation induced by long-standing GERD results in intestinal metaplasia, a premalignant condition known as Barrett's esophagus. The metaplastic epithelium is predisposed to malignancy, and most esophageal adenocarcinomas are judged to arise from Barrett's esophagus.
Epithelial cells produce IGFII, a potent mitogen which stimulates cell growth and prevents apoptosis. Animal and human studies have demonstrated upregulation of IGFII in chronic inflammatory processes as well as in precancerous and cancerous lesions. In response to acute injury, elevated levels of IGFII have been demonstrated in skin epidermis and uroepithelium suggesting that IGFII plays a role in epithelial regeneration. Overexpression of IGFII has also been detected in many human tumors including colorectal carcinomas, Wilms tumor, rhabdomyosarcoma, breast, and hepatocellular carcinoma. In addition, elevated levels of IGFII have been detected in precancerous lesions of the colon and liver in both animal and human studies. Moreover, in patients with hepatitis C related chronic active hepatitis, cirrhosis and hepatocellular carcinoma, IGFII expression levels progressively increased from normal liver to chronic hepatitis and cirrhosis, and remained persistently elevated in precancerous liver lesions and hepatocellular carcinoma suggesting that IGFII plays a role in the development of malignancy in the setting of chronic inflammation.
IGFII is known to be genomically imprinted. Genomic imprinting is a reversible modification of DNA that allows gene expression from only one of two alleles. IGFII overexpression occurs in esophageal squamous carcinomas, and exogenous IGFII enhances the growth of esophageal squamous carcinoma cell lines. Loss of imprinting (LOI), which would allow bi-allelic expression of the IGFII gene, is one mechanism that could account for the increased levels of IGFII in human esophageal tumors. Using real time PCR of biopsy samples obtained from patients with Barrett's esophagus, we will compare the expression of IGFII in the Barrett's epithelium to that of squamous esophagus, stomach, and duodenum. In addition, using allele specific PCR we will attempt to identify LOI as the mechanism for IGFII overexpression. Once identified in patient biopsy samples, the importance of IGFII to the physiologic parameters of proliferation and apoptosis will investigated in vitro in a cell culture system using Barrett's esophageal cells immortalized by telomerase.

Previous Research Activities or Publications with Medical Students:
Gavin Brown (student at UT-San Antonio, Summer of 1999 (not part of the SUMR program) and 2000

William Schmalstieg UTSW medical student, summer of 2001. Will presented a poster of distinction at the international meeting of the American Gastroenterological Association in May of 2002 as a result of his summer work.

Publications with medical students: R. Appel performed research while applying to medical school at the University of Maryland. She entered medical school at UMD the following year.

1. Lei, J., Zou, T-T, Shi, Y-Q, Zhou, X-L., Smolinski, K.N., Yin, J., Souza, R.F., Appel, R., Wang, S., Cymes, K., Chan, O., Abraham, J.M., Harpaz, N., and Meltzer, S.M. Infrequent DPC4 gene mutation in esophageal cancer, gastric cancer and ulcerative colitis-associated neoplasms. Oncogene, 13: 2459-2462, 1996.
2. Souza, R.F., Appel, R., Yin, J., Wang, S., Smolinski, K.N., Abraham, J.M., Zou, T-T., Shi, Y-Q., Lei, J., Cottrell, J., Cymes, K., Biden, K., Simms, L., Leggett, B., Lynch, P.M., Frazier, M., Powell, S.M., Harpaz, N., Sugimura, H., Young, J., and Meltzer, S.J. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumors. Nature Genetics, 14: 255-257, 1996.
3. Souza, R.F., Lei, J., Yin, J., Appel, R., Zou, T-T., Zhou, X-L., Wang, S., Rhyu, M-G., Cymes, K., Chan, O., Park, W-S., Krasna, M.J., Greenwald, B.D., Cottrell, J., Abraham, J.M., Simms, L., Leggett, B. et al. A Transforming Growth Factor 1 Receptor Type II Mutation in Ulcerative Colitis-Associated Neoplasms. Gastroenterology, 112: 40-45, 1997.
4. Simms, L., Zou, T-T., Shi, Y-Q., Lei, J., Appel, R., Souza ,R.F., Young, J., Meltzer, S.J., Leggett, B.A. Apparent protection from instability of repeat sequences in cancer related genes in replication error positive gastrointestinal cancers. Oncogene, 14: 2613-2618, 1997.

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