Proteomic screening of a cell line model of esophageal carcinogenesis identifies cathepsin D and aldo-keto reductase 1C2 and 1B10 dysregulation in Barrett's esophagus and esophageal adenocarcinoma.
Esophageal adenocarcinoma (EA) incidence is increasing rapidly and is associated with a poor prognosis. Identifying biomarkers of disease development and progression would be invaluable tools to inform clinical practice. Two-dimensional polyacrylamide gel electrophoresis was used to screen 10 esophageal cell lines representing distinct stages in the development of esophageal cancer. Thirty-three proteins were identified by MALDI-TOF-MS which demonstrated differences in expression across the cell lines. Western blotting and qRT-PCR confirmed increased cathepsin D and aldo-keto reductases 1C2 and 1B10 expression in metaplastic and dysplastic cell lines. Expression of these proteins was further assessed in esophageal epithelium from patients with nonerosive (NERD) and erosive gastro-esophageal reflux disease, Barrett's esophagus (BE) and EA. When compared with normal epithelium of NERD patients, (i) cathepsin D mRNA levels demonstrated a stepwise increase in expression (p<0.05) in erosive, metaplastic and EA tissue; (ii) AKR1B10 expression increased (p<0.05) 3- and 9-fold in erosive and Barrett's epithelium, respectively; and (iii) AKR1C2 levels increased (p<0.05) in erosive and Barrett's epithelium, but were reduced (p<0.05) in EA. These proteins may contribute to disease development via effects on apoptosis, transport of bile acids and retinoid metabolism and should be considered as candidates for further mechanistic and clinical investigations.
Breton
Jean
J
Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute of Genetics, Health and Therapeutics, Clarendon Way, University of Leeds, Leeds LS2 9JT, United Kingdom.
Gage
Matthew C
MC
Hay
Alastair W
AW
Keen
Jeffrey N
JN
Wild
Christopher P
CP
Donnellan
Clare
C
Findlay
John B C
JB
Hardie
Laura J
LJ
D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism*; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D001471:Barrett Esophagus / Q000175:diagnosis / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015180:Electrophoresis, Gel, Two-Dimensional; D004938:Esophageal Neoplasms / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011379:Prognosis; D020543:Proteome / Q000032:analysis*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D014408:Biomarkers, Tumor; D002402:Cathepsin D; D006913:Hydroxysteroid Dehydrogenases; D020543:Proteome; C120471:AKR1B10 protein, human; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)