Skip to main content
SpringerLink
Log in

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

  • Research
  • Published:
Pathology & Oncology Research

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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):302–317

    PubMed  Google Scholar 

  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):36–46

    Article  CAS  PubMed  Google Scholar 

  3. Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66(7):606–630

    Article  CAS  PubMed  Google Scholar 

  4. Harrison EH (2012) Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Biochim Biophys Acta 1821(1):70–77

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Napoli JL (2012) Physiological insights into all-trans-retinoic acid biosynthesis. Biochim Biophys Acta 1821(1):152–167

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):198–205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):3936–3949

    Article  PubMed Central  PubMed  Google Scholar 

  8. Duester G, Farrés J, Felder MR et al (1999) Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family. Biochem Pharmacol 58(3):389–395

    Article  CAS  PubMed  Google Scholar 

  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):338–342

    Article  CAS  PubMed  Google Scholar 

  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):101–109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):13804–13811

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):5337–5342

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):20299–20308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):973–979

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ross AC, Zolfaghari R (2011) Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu Rev Nutr 31:65–87

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Bushue N, Wan YJ (2010) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62(13):1285–1298

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):30490–30495

    Article  CAS  PubMed  Google Scholar 

  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):39–45

    Article  CAS  PubMed  Google Scholar 

  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):53–60

    Article  CAS  PubMed  Google Scholar 

  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):1050–1064

    Article  CAS  PubMed  Google Scholar 

  21. Parlesak A, Menzl I, Feuchter A, Bode JC, Bode C (2000) Inhibition of retinol oxidation by ethanol in the rat liver and colon. Gut 47(6):825–831

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):34397–34405

    Article  CAS  PubMed  Google Scholar 

  23. Pasquali D, Thaller C, Eichele G (1996) Abnormal level of retinoic acid in prostate cancer tissues. J Clin Endocrinol Metab 81(6):2186–2191

    CAS  PubMed  Google Scholar 

  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):302–309

    Article  PubMed  Google Scholar 

  25. Williams SJ, Cvetkovic D, Hamilton TC (2009) Vitamin A metabolism is impaired in human ovarian cancer. Gynecol Oncol 112(3):637–645

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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–G433

    Article  CAS  PubMed  Google Scholar 

  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):1776–1785

    Article  CAS  PubMed  Google Scholar 

  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):37–49

    Article  CAS  PubMed  Google Scholar 

  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):577–585

    Article  CAS  PubMed  Google Scholar 

  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):594–604

    Article  CAS  PubMed  Google Scholar 

  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 148:2914–2924

    Article  PubMed  Google Scholar 

  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):e30698

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):652–659

    Article  CAS  PubMed  Google Scholar 

  34. Boleda MD, Julià P, Moreno A, Parés X (1989) Role of extrahepatic alcohol dehydrogenase in rat ethanol metabolism. Arch Biochem Biophys 274(1):74–81

    Article  CAS  PubMed  Google Scholar 

  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):37–49

    Article  CAS  PubMed  Google Scholar 

  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):571–580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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):943–950

    Article  CAS  PubMed  Google Scholar 

  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):317–330

    Article  CAS  Google Scholar 

  40. Kropotova ES, Tychko RA, Zinov’eva OL et al (2010) Downregulation of AKR1B10 gene expression in colorectal cancer. Mol Biol (Mosk) 44(2):243–250

    Article  CAS  Google Scholar 

  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):427–433

    CAS  PubMed  Google Scholar 

  42. Martin HJ, Maser E (2009) Role of human aldo-ketoreductase AKR1B10 in the protection against toxic aldehydes. Chem Biol Interact 178(1–3):145–150

    Article  CAS  PubMed  Google Scholar 

  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):1212–1223

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The Authors thank Nikolai Lisitsyn for critical review of the manuscript. This work was supported by the Russian Foundation for Basic Research (project nos. 10-04-01760a and 12-04-00388a).

Conflict of Interest

The Authors declare that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russian Federation

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

Authors
  1. Ekaterina S. Kropotova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olga L. Zinovieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alisa F. Zyryanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vera I. Dybovaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vladimir S. Prasolov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sergey F. Beresten
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nina Yu. Oparina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tamara D. Mashkova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tamara D. Mashkova.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1

(DOC 50 kb)

Table S2

(DOCX 23 kb)

Table S3

(DOC 36 kb)

Table S4

(DOC 58 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kropotova, E.S., Zinovieva, O.L., Zyryanova, A.F. et al. Altered Expression of Multiple Genes Involved in Retinoic Acid Biosynthesis in Human Colorectal Cancer. Pathol. Oncol. Res. 20, 707–717 (2014). https://doi.org/10.1007/s12253-014-9751-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-014-9751-4

Keywords

Search

Navigation