title: Sorbitol dehydrogenase overexpression and other aspects of dysregulated protein expression in human precancerous colorectal neoplasms: a quantitative proteomics study.
abstract: Colorectal adenomas are cancer precursor lesions of the large bowel. A multitude of genomic and epigenomic changes have been documented in these preinvasive lesions, but their impact on the protein effectors of biological function has not been comprehensively explored. Using shotgun quantitative MS, we exhaustively investigated the proteome of 30 colorectal adenomas and paired samples of normal mucosa. Total protein extracts were prepared from these tissues (prospectively collected during colonoscopy) and from normal (HCEC) and cancerous (SW480, SW620, Caco2, HT29, CX1) colon epithelial cell lines. Peptides were labeled with isobaric tags (iTRAQ 8-plex), separated via OFFGEL electrophoresis, and analyzed by means of LC-MS/MS. Nonredundant protein families (4325 in tissues, 2017 in cell lines) were identified and quantified. Principal component analysis of the results clearly distinguished adenomas from normal mucosal samples and cancer cell lines from HCEC cells. Two hundred and twelve proteins displayed significant adenoma-related expression changes (q-value < 0.02, mean fold change versus normal mucosa ±1.4), which correlated (r = 0.74) with similar changes previously identified by our group at the transcriptome level. Fifty-one (∼25%) proteins displayed directionally similar expression changes in colorectal cancer cells (versus HCEC cells) and were therefore attributed to the epithelial component of adenomas. Although benign, adenomas already exhibited cancer-associated proteomic changes: 69 (91%) of the 76 protein up-regulations identified in these lesions have already been reported in cancers. One of the most striking changes involved sorbitol dehydrogenase, a key enzyme in the polyol pathway. Validation studies revealed dramatically increased sorbitol dehydrogenase concentrations and activity in adenomas and cancer cell lines, along with important changes in the expression of other enzymes in the same (AKR1B1) and related (KHK) pathways. Dysregulated polyol metabolism might represent a novel facet of metabolome remodeling associated with tumorigenesis.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland;
authors.forename: Anuli
authors.initials: A
authors.lastname: Uzozie
authors.forename: Paolo
authors.initials: P
authors.lastname: Nanni
authors.forename: Teresa
authors.initials: T
authors.lastname: Staiano
authors.forename: Jonas
authors.initials: J
authors.lastname: Grossmann
authors.forename: Simon
authors.initials: S
authors.lastname: Barkow-Oesterreicher
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Amit
authors.initials: A
authors.lastname: Tiwari
authors.forename: Federico
authors.initials: F
authors.lastname: Buffoli
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D000449:Aldehyde Reductase / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005631:Fructokinases / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D007064:L-Iditol 2-Dehydrogenase; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase; D005631:Fructokinases; C021475:ketohexokinase