title: Altered expression of multiple genes involved in retinoic acid biosynthesis in human colorectal cancer.
abstract: All-trans-retinoic acid (atRA), the oxidized form of vitamin A (retinol), regulates a wide variety of biological processes, such as cell proliferation and differentiation. Multiple alcohol, retinol and retinaldehyde dehydrogenases (ADHs, RDHs, RALDHs) as well as aldo-keto reductases (AKRs) catalyze atRA production. The reduced atRA biosynthesis has been observed in several human tumors, including colorectal cancer. However, subsets of atRA-synthesizing enzymes have not been determined in colorectal tumors. We investigated the expression patterns of genes involved in atRA biosynthesis in normal human colorectal tissues, primary carcinomas and cancer cell lines by RT-PCR. These genes were identified using transcriptomic data analysis (expressed sequence tags, RNA-sequencing, microarrays). Our results indicate that each step of the atRA biosynthesis pathway is dysregulated in colorectal cancer. Frequent and significant decreases in the mRNA levels of the ADH1B, ADH1C, RDHL, RDH5 and AKR1B10 genes were observed in a majority of colorectal carcinomas. The expression levels of the RALDH1 gene were reduced, and the expression levels of the cytochrome CYP26A1 gene increased. The human colon cancer cell lines showed a similar pattern of changes in the mRNA levels of these genes. A dramatic reduction in the expression of genes encoding the predominant retinol-oxidizing enzymes could impair atRA production. The most abundant of these genes, ADH1B and ADH1C, display decreased expression during progression from adenoma to early and more advanced stage of colorectal carcinomas. The diminished atRA biosynthesis may lead to alteration of cell growth and differentiation in the colon and rectum, thus contributing to the progression of colorectal cancer.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russian Federation.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Kropotova
authors.forename: Olga L
authors.initials: OL
authors.lastname: Zinovieva
authors.forename: Alisa F
authors.initials: AF
authors.lastname: Zyryanova
authors.forename: Vera I
authors.initials: VI
authors.lastname: Dybovaya
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Prasolov
authors.forename: Sergey F
authors.initials: SF
authors.lastname: Beresten
authors.forename: Nina Yu
authors.initials: NY
authors.lastname: Oparina
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Mashkova
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000426:Alcohol Dehydrogenase / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000449:Aldehyde Reductase / Q000235:genetics; D000074408:Aldo-Keto Reductases; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D016208:Databases, Factual; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012007:Rectum / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D014212:Tretinoin; D015096:3-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases; C432414:DHRS9 protein, human; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; C489332:ADH1B protein, human; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase; C105846:retinol dehydrogenase 5; D000449:Aldehyde Reductase