عنوان

Molecular abnormalities in Syrian golden hamster pancreatic ductal adenocarcinomas

TLpq304227090

انگلیسی

Molecular abnormalities in Syrian golden hamster pancreatic ductal adenocarcinomas

[Thesis]

K.-W. Chang

D. G. Scarpelli

Northwestern University

1995

109

Ph.D.

Northwestern University

1995

This study examines the involvement of the tumor suppressor genes p53, DCC and Rb-1 and the oncogene mdm2, as well as the growth factor TGF-usd\alphausd in the Syrian golden hamster pancreatic ductal adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine. Hamster p53 sequence for the genomic regions surrounding exons 5 through 8, and the partial coding sequence of mdm2, glyceraldehyde-3-phosphate dehydrogenase (G3PDH) gene and DCC were determined. Immunohistochemistry and single strand conformation polymorphism analysis showed no evidence of p53 mutation in 21 grossly evident tumors subjected to both molecular and morphological analysis, nor was it detected by immunohistochemical study of an additional 42 adenocarcinomas that were not grossly evident. A hamster mdm2 specific riboprobe was generated from the cDNA sequence for ribonuclease protection assays. After normalization to G3PDH expression, 5/19 test pairs presented overexpression of mdm2 mRNA in carcinomas when compared to adjacent grossly normal pancreas. The expression of DCC and Rb-1 in hamster pancreatic adenocarcinomas was analyzed by semi-quantitative RT-PCR under conditions optimized to insure a valid analysis. Ten of 19 neoplasms showed a complete or partial loss of DCC expression while 8 showed similar losses of Rb-1 expression when compared to matched controls. Using immunohistochemistry, 76% of the gross tumors and 60% of total tumors showed TGF-usd\alphausd overexpression. TGF-usd\alphausd overexpression was also found in 33% of preneoplastic lesions. These results support the multiple-hit hypothesis in the pathogenesis of pancreatic carcinogenesis in the Syrian golden hamster model. A 90% incidence of K-ras mutation and the absence of p53 mutations are prominent features of hamster pancreatic ductal adenocarcinomas. Our observations indicate the involvement of mdm2 deregulation in 26% of tumors that lack p53 mutation and the underexpression of DCC in 53% and Rb-1 in 42% as well as overexpression of TGF-usd\alphausd. Deregulation of TGF-usd\alphausd appears to be as crucial as the K-ras mutation as indicated by its frequent and sustained presence through the various phases of hamster pancreatic duct carcinogenesis.

Biological sciences

Genetics

Health and environmental sciences

Pathology

Pathology

D. G. Scarpelli

K.-W. Chang

p

[Thesis]

276903

a

Y