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Pathology & Oncology Research
Published in: Pathology & Oncology Research 3/2014

01-07-2014 | Research

Altered Expression of Multiple Genes Involved in Retinoic Acid Biosynthesis in Human Colorectal Cancer

Authors: Ekaterina S. Kropotova, Olga L. Zinovieva, Alisa F. Zyryanova, Vera I. Dybovaya, Vladimir S. Prasolov, Sergey F. Beresten, Nina Yu. Oparina, Tamara D. Mashkova

Published in: Pathology & Oncology Research | Issue 3/2014

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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.
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Literature
1.
Di Caro V, Phillips B, Engman C, Harnaha J, Trucco M, Giannoukakis N (2013) Retinoic acid-producing, ex-vivo-generated human tolerogenic dendritic cells induce the proliferation of immunosuppressive B lymphocytes. Clin Exp Immunol 174(2):302–317PubMed
2.
Morikawa K, Hanada H, Hirota K, Nonaka M, Ikeda C (2013) All-trans retinoic acid displays multiple effects on the growth, lipogenesis and adipokine gene expression of AML-I preadipocyte cell line. Cell Biol Int 37(1):36–46PubMedCrossRef
3.
Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66(7):606–630PubMedCrossRef
4.
Harrison EH (2012) Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Biochim Biophys Acta 1821(1):70–77PubMedCentralPubMedCrossRef
5.
6.
Kumar S, Sandell LL, Trainor PA, Koentgen F, Duester G (2012) Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models. Biochim Biophys Acta 1821(1):198–205PubMedCentralPubMedCrossRef
7.
Parés X, Farrés J, Kedishvili N, Duester G (2008) Medium- and short-chain dehydrogenase/reductase gene and protein families: medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism. Cell Mol Life Sci 65(24):3936–3949PubMedCentralPubMedCrossRef
8.
Duester G, Farrés J, Felder MR et al (1999) Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family. Biochem Pharmacol 58(3):389–395PubMedCrossRef
9.
Estonius M, Svensson S, Höög J-O (1996) Alcohol dehydrogenase in human tissues: localization of transcripts coding for five classes of the enzyme. FEBS Lett 397(2–3):338–342PubMedCrossRef
10.
Gallego O, Belyaeva OV, Porté S et al (2006) Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases/reductases and aldo-keto reductases with retinoids. Biochem J 399(1):101–109PubMedCentralPubMedCrossRef
11.
Molotkov A, Deltour L, Foglio MH, Cuenca AE, Duester G (2002) Distinct retinoid metabolic functions for alcohol dehydrogenase genes Adh1 and Adh4 in protection against vitamin A toxicity or deficiency revealed in double null mutant mice. J Biol Chem 277(16):13804–13811PubMedCentralPubMedCrossRef
12.
Molotkov A, Fan X, Deltour L et al (2002) Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proc Natl Acad Sci U S A 99(8):5337–5342PubMedCentralPubMedCrossRef
13.
Belyaeva OV, Johnson MP, Kedishvili NY (2008) Kinetic analysis of human enzyme RDH10 defines the characteristics of a physiologically relevant retinol dehydrogenase. J Biol Chem 283(29):20299–20308PubMedCentralPubMedCrossRef
14.
Crosas B, Hyndman DJ, Gallego O, Martras S, Parés X, Flynn TG, Farrés J (2003) Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: Consequences for retinoid metabolism. Biochem J 373(Pt 3):973–979PubMedCentralPubMedCrossRef
15.
16.
17.
Nadauld LD, Shelton DN, Chidester S, Yost HJ, Jones DA (2005) The zebrafish retinol dehydrogenase, rdh1l, is essential for intestinal development and is regulated by the tumor suppressor adenomatous polyposis coli. J Biol Chem 280(34):30490–30495PubMedCrossRef
18.
Niles RM, Wilhelm SA, Thomas P, Zamcheck N (1988) The effect of sodium butyrate and retinoic acid on growth and CEA production in a series of human colorectal tumor cell lines representing different states of differentiation. Cancer Invest 6(1):39–45PubMedCrossRef
19.
Reynolds S, Rajagopal S, Chakrabarty S (1998) Differentiation-inducing effect of retinoic acid, difluoromethylornithine, sodium butyrate and sodium suramin in human colon cancer cells. Cancer Lett 134(1):53–60PubMedCrossRef
20.
Ang HL, Deltour L, Zgombić-Knight M, Wagner MA, Duester G (1996) Expression patterns of class I and class IV alcohol dehydrogenase genes in developing epithelia suggest a role for alcohol dehydrogenase in local retinoic acid synthesis. Alcohol Clin Exp Res 20(6):1050–1064PubMedCrossRef
21.
22.
Jette C, Peterson PW, Sandoval IT, Manos EJ, Hadley E, Ireland CM, Jones DA (2004) The tumor suppressor adenomatous polyposis coli and caudal related homeodomain protein regulate expression of retinol dehydrogenase L. J Biol Chem 279(33):34397–34405PubMedCrossRef
23.
Pasquali D, Thaller C, Eichele G (1996) Abnormal level of retinoic acid in prostate cancer tissues. J Clin Endocrinol Metab 81(6):2186–2191PubMed
24.
Mira-y-Lopez R, Zheng WL, Kuppumbatti YS, Rexer B, Jing Y, Ong DE (2000) Retinol conversion to retinoic acid is impaired in breast cancer cell lines relative to normal cells. J Cell Physiol 185(2):302–309PubMedCrossRef
25.
26.
Matsumoto M, Yokoyama H, Suzuki H, Shiraishi-Yokoyama H, Hibi T (2005) Retinoic acid formation from retinol in the human gastric mucosa: role of class IV alcohol dehydrogenase and its relevance to morphological changes. Am J Physiol Gastrointest Liver Physiol 289(3):G429–G433PubMedCrossRef
27.
Fukumoto S, Yamauchi N, Moriguchi H et al (2005) Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers’ non-small cell lung carcinomas. Clin Cancer Res 11(5):1776–1785PubMedCrossRef
28.
Chiang CP, Jao SW, Lee SP et al (2012) Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer. Alcohol 46(1):37–49PubMedCrossRef
29.
Zaitseva M, Vollenhoven BJ, Rogers PA (2007) Retinoic acid pathway genes show significantly altered expression in uterine fibroids when compared with normal myometrium. Mol Hum Reprod 13(8):577–585PubMedCrossRef
30.
Ashla AA, Hoshikawa Y, Tsuchiya H et al (2010) Genetic analysis of expression profile involved in retinoid metabolism in non-alcoholic fatty liver disease. Hepatol Res 40(6):594–604PubMedCrossRef
31.
O’Shaughnessy PJ, Abel M, Charlton HM, Hu B, Johnston H, Baker PJ (2007) Altered expression of genes involved in regulation of vitamin A metabolism, solute transportation, and cytoskeletal function in the androgen-insensitive tfm mouse testis. Endocrinology 148:2914–2924PubMedCrossRef
32.
Sandell LL, Lynn ML, Inman KE, McDowell W, Trainor PA (2012) RDH10 oxidation of Vitamin A is a critical control step in synthesis of retinoic acid during mouse embryogenesis. PLoS One 7(2):e30698PubMedCentralPubMedCrossRef
33.
Collins MD, Eckhoff C, Chahoud I, Bochert G, Nau H (1992) 4-Methylpyrazole partially ameliorated the teratogenicity of retinol and reduced the metabolic formation of all-trans-retinoic acid in the mouse. Arch Toxicol 66(9):652–659PubMedCrossRef
34.
Boleda MD, Julià P, Moreno A, Parés X (1989) Role of extrahepatic alcohol dehydrogenase in rat ethanol metabolism. Arch Biochem Biophys 274(1):74–81PubMedCrossRef
35.
Chiang CP, Jao SW, Lee SP, Chen PC, Chung CC, Lee SL, Nieh S, Yin SJ (2012) Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer. Alcohol 46(1):37–49PubMedCrossRef
36.
Chase JR, Poolman MG, Fell DA (2009) Contribution of NADH increases to ethanol’s inhibition of retinol oxidation by human ADH isoforms. Alcohol Clin Exp Res 33(4):571–580PubMedCentralPubMedCrossRef
37.
Mashkova TD, Oparina NIu, Zinov’eva OL et al (2006) Transcription of TIMP3, DAPK1, and AKR1B10 in squamous cell lung cancer. Mol Biol (Mosk) 40(6):1047–1054
38.
Scuric Z, Stain SC, Anderson WF, Hwang JJ (1998) New member of aldose reductase family proteins overexpressed in human hepatocellular carcinoma. Hepatology 27(4):943–950PubMedCrossRef
39.
Kropotova ES, Zinov’eva OL, Zyrianova AF et al (2013) Expression of genes involved in retinoic acid biosynthesis in human gastric cancer. Mol Biol (Mosk) 47(2):317–330CrossRef
40.
Kropotova ES, Tychko RA, Zinov’eva OL et al (2010) Downregulation of AKR1B10 gene expression in colorectal cancer. Mol Biol (Mosk) 44(2):243–250CrossRef
41.
Roberts ES, Vaz AD, Coon MJ (1992) Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal. Mol Pharmacol 41(2):427–433PubMed
42.
Martin HJ, Maser E (2009) Role of human aldo-ketoreductase AKR1B10 in the protection against toxic aldehydes. Chem Biol Interact 178(1–3):145–150PubMedCrossRef
43.
Westerlund M, Belin AC, Felder MR, Olson L, Galter D (2007) High and complementary expression patterns of alcohol and aldehyde dehydrogenases in the gastrointestinal tract: implications for Parkinson’s disease. FEBS J 274(5):1212–1223PubMedCrossRef
Metadata
Title
Altered Expression of Multiple Genes Involved in Retinoic Acid Biosynthesis in Human Colorectal Cancer
Authors
Ekaterina S. Kropotova
Olga L. Zinovieva
Alisa F. Zyryanova
Vera I. Dybovaya
Vladimir S. Prasolov
Sergey F. Beresten
Nina Yu. Oparina
Tamara D. Mashkova
Publication date
01-07-2014
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 3/2014
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-014-9751-4

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