Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus.
Neoplastic progression in Barrett's esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27(kip1) protein, but did not display appreciable nuclear staining for p16(kip4), p21(cip1) or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16(kip4) (74%), p21(cip1) (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16(kip4) and cyclin E, and p21(cip1) and p27(kip4) with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.
Umansky
M
M
GI Oncology Unit, Tel Aviv Medical Center and Tel Aviv University, Israel.
Yasui
W
W
Hallak
A
A
Brill
S
S
Shapira
I
I
Halpern
Z
Z
Hibshoosh
H
H
Rattan
J
J
Meltzer
S
S
Tahara
E
E
Arber
N
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001471:Barrett Esophagus / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism
D000897:Anti-Ulcer Agents; C493956:CDKN1A protein, human; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; C413374:p27 antigen; D019938:Cyclin D1