Skip to main content
SpringerLink
Log in

Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer

  • Genomics. Transcriptomics
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Retinoids are signaling molecules that control a wide variety of cellular processes and possess antitumor activity. This work presents a comprehensive description of changes in the expression of 23 genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer tumors compared to adjacent normal tissues obtained using RT-PCR. Even at early stages of malignant transformation, a significant decrease in ADH1B, ADH3, RDHL, and RALDH1 mRNA levels was observed in 82, 79, 73, and 64% of tumor specimens, respectively, and a considerable increase in AKR1B10 mRNA content was observed in 80% of tumors. Dramatic changes in the levels of these mRNAs can impair the synthesis of all-trans retinoic acid, a key natural regulatory retinoid. Apart from that, it was found that mRNA levels of nuclear retinoid receptor genes RXRγ, RARα, RXRα, and gene RDH11 were significantly decreased in 80, 67, 57, and 66% of tumor specimens, respectively. Thus, neoplastic transformation of lung tissue cells is accompanied with deregulated expression of key genes of retinoid metabolism and function.

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.

Similar content being viewed by others

Abbreviations

ADH:

alcohol dehydrogenase

AKR:

aldo-keto reductase

ATRA:

all-trans retinoic acid

CRABP1-2:

cellular retinoic acid-binding proteins 1 and 2

CRBP1:

cellular retinolbinding protein 1

CYP26A1, B1, C1:

enzymes of the CYP26 family (cytochrome P450-dependent monooxygenases)

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

EST:

expressed sequence tags

NSCLC:

non-small-cell lung cancer

LC:

lung cancer

RALDH:

retinaldehyde dehydrogenase

RAR:

retinoic acid receptor

RDH:

retinol dehydrogenase

RXR:

retinoid X receptor

PCR:

polymerase chain reaction

RT-PCR:

reverse transcription with subsequent PCR

RT-qPCR:

quantitative RT-PCR in real time

References

  1. Blomhoff R., Blomhoff H.K. 2006. Overview of retinoid metabolism and function. J. Neurobiol. 66, 606–630.

    Article  CAS  PubMed  Google Scholar 

  2. Tang X.H., Gudas L.J. 2011. Retinoids, retinoic acid receptors, and cancer. Annu. Rev. Pathol. 6, 345–364.

    Article  CAS  PubMed  Google Scholar 

  3. di Masi A., Leboffe L., De Marinis E., Pagano F., Cicconi L., Rochette-Egly C., Lo-Coco F., Ascenzi P., Nervi C. 2015. Retinoic acid receptors: From molecular mechanisms to cancer therapy. Mol. Aspects Med. 41, 1–115.

    Article  PubMed  Google Scholar 

  4. Watters K.M., Bryan K., Foley N.H., Meehan M., Stallings R.L. 2013. Expressional alterations in functional ultra-conserved non-coding RNAs in response to all-trans retinoic acid-induced differentiation in neuroblastoma cells. BMC Cancer. 13, 184–196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cawley S., Bekiranov S., Ng H.H., Kapranov P., Sekinger E.A., Kampa D., Piccolboni A., Sementchenko V., Cheng J., Williams A.J., Wheeler R., Wong B., Drenkow J., Yamanaka M., Patel S., et al. 2004. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell. 116, 499–509.

    Article  CAS  PubMed  Google Scholar 

  6. Blamer J.E., Blomhoff R. 2002. Gene expression regulation by retinoic acid. J. Lipid Res. 43, 1773–1782.

    Article  Google Scholar 

  7. Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D. 2011. Global cancer statistics. CA Cancer J. Clin. 61, 69–90.

    Article  PubMed  Google Scholar 

  8. Davydov M.I., Aksel’ E.M. 2014. Statistika zlokachestvennykh novoobrazovanii v Rossii i stranakh SNG v 2012 g. (Statistics of Malignant Neoplasms in Russis and CIS Countries in 2012), Moscow: RONTs RAMN.

    Google Scholar 

  9. Chytil F. 1996. Retinoids in lung development. FASEB J. 10, 986–992.

    CAS  PubMed  Google Scholar 

  10. Mark M., Ghyselinck N.B., Chambon P. 2009. Function of retinoic acid receptors during embryonic development. Nucl. Recept. Signal. 7, e002.

    PubMed  PubMed Central  Google Scholar 

  11. Sporn M.B., Dunlop N.M., Newton D.L., Smith J.M., 1976. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed. Proc. 35, 1332–1338.

    CAS  PubMed  Google Scholar 

  12. Chen F., Cao Y., Qian J., Shao F., Niederreither K., Cardoso W.V. 2010. A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J. Clin. Invest. 120, 2040–2048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Siddikuzzaman, Grace V.M. 2012. Inhibition of metastatic lung cancer in C57BL/6 mice by liposome encapsulated all-trans retinoic acid (ATRA). Int. Immunopharmacol. 14, 570–579.

    Article  CAS  PubMed  Google Scholar 

  14. Ramya D., Siddikuzzaman, Grace V.M. 2012. Effect of all-trans retinoic acid (ATRA) on syndecan-1 expression and its chemoprotective effect in benzo(alpha)pyreneinduced lung cancer mice model. Immunopharmacol. Immunotoxicol. 34, 1020–1027.

    Article  CAS  PubMed  Google Scholar 

  15. Bushue N., Wan Y.J. 2010. Retinoid pathway and cancer therapeutics. Adv. Drug Deliv. 62, 1285–1298.

    Article  CAS  Google Scholar 

  16. Lokshin A., Zhang H., Mayotte J., Lokshin M., Levitt M.L. 1999. Early effects of retinoic acid on proliferation, differentiation and apoptosis in non-small cell lung cancer cell lines. Anticancer Res. 19, 5251–5254.

    CAS  PubMed  Google Scholar 

  17. Guchelaar H.J., Timmer-Bosscha H., Dam-Meiring A., Uges D.R., Oosterhuis J.W., de Vries E.G., Mulder N.H. 1993. Enhancement of cisplatin and etoposide cytotoxicity after all-trans retinoic acid-induced cellular differentiation of a murine embryonal carcinoma cell line. Int. J. Cancer. 55, 442–447.

    Article  CAS  PubMed  Google Scholar 

  18. Smith M.A., Parkinson D.R., Cheson B.D., Friedman M.A. 1992. Retinoids in cancer therapy. J. Clin. Oncol. 10, 839–864.

    CAS  PubMed  Google Scholar 

  19. Arrieta O., Gonzalez-De la Rosa C.H., Rechaga-Ocampo E., Villanueva-Rodriguez G., Ceron-Lizarraga T.L., Martinez-Barrera L., Vázquez-Manríquez M.E., Ríos-Trejo M.A., Alvarez-Avitia M.A., Hernández-Pedro N., Rojas-Marín C., De la Garza J. 2010. Randomized phase II trial of all-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 3463–3471.

    Article  CAS  PubMed  Google Scholar 

  20. Dragnev K.H., Petty W.J., Shah S., Biddle A., Desai N.B., Memoli V., Rigas J.R., Dmitrovsky E.J. 2005. Bexarotene and erlotinib for aerodigestive tract cancer. Clin. Oncol. 23, 8757–8764.

    Article  CAS  Google Scholar 

  21. Napoli J.L. 2012. Physiological insights into all-transretinoic-acid biosynthesis. Biochim. Biophys. Acta. 1821, 152–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kumar S., Sandell L.L., Trainor P.A., Koentgen F., Duester G. 2012. Alcohol and aldehyde dehydrogenases: Retinoid metabolic effects in mouse knockout models. Biochim. Biophys. Acta. 1821, 198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chevkina E.M., Favorskaya I.A. 2015. CRABP proteins: Relatives or namesakes? Usp. Mol. Onkol. 2, 6–16.

    Article  Google Scholar 

  24. Mashkova T.D., Oparina N.Yu., Zinov’eva O.L., Kropotova E.S., Dubovaya V.I., Poltaraus A.B., Fridman M.V., Kopantsev E.P., Vinogradova T.V., Zinov’eva M.V., Laktionov K.K., Kasymova O.T., Zborovskaya I.B., Sverdlov E.D., Kiselev L.L. 2006. Transcription of TIMP3, DAPK1, and AKR1B10 in squamous-cell lung cancer. Mol. Biol. (Moscow). 40 (6), 1047–1054.

    Article  CAS  Google Scholar 

  25. Kopantzev E.P., Monastyrskaya G.S., Vinogradova T.V., Zinovyeva M.V., Kostina M.B., Filyukova O.B., Tonevitsky A.G., Sukhikh G.T., Sverdlov E.D. 2008. Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma. Lung Cancer. 62 (1), 23–34.

    Article  PubMed  Google Scholar 

  26. Kropotova E.S., Zinovieva O.L., Zyryanova A.F., Dybovaya V.I., Prasolov V.S., Beresten S.F., Oparina N.Y., Mashkova T.D. 2014. Altered expression of multiple genes involved in retinoic acid biosynthesis in human colorectal cancer. Pathol. Oncol. Res. 20, 707–717.

    Article  CAS  PubMed  Google Scholar 

  27. Kropotova E.S., Zinov’eva O.L., Zyryanova A.F., Choinzonov E.L., Afanas’ev S.G., Cherdyntseva N.V., S.F. Beresten’ S.F., Oparina N.Yu., Mashkova T.D. 2013. Expression of genes involved in retinoic acid biosynthesis in human gastric cancer. Mol. Biol. (Moscow). 47 (2), 317–330.

    Article  CAS  Google Scholar 

  28. Brabender J., Metzger R., Salonga D., Danenberg K.D., Danenberg P.V., Hölscher A.H., Schneider P.M. 2005. Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: Implications for tumor development and prognosis. Carcinogenesis. 26, 525–530.

    Article  CAS  PubMed  Google Scholar 

  29. Inui N., Sasaki S., Suda T., Chida K., Nakamura H. 2003. The loss of retinoic acid receptor alpha, beta and alcohol dehydrogenase3 expression in non-small cell lung cancer. Respirology. 8, 302–309.

    Article  PubMed  Google Scholar 

  30. Massaro G.D., Massaro D. 1997. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat. Med. 3, 675–677.

    Article  CAS  PubMed  Google Scholar 

  31. Liu B., Harvey C.S., McGowan S.E. 1993. Retinoic acid increases elastin in neonatal rat lung fibroblast cultures. Am. J. Physiol. 265, L430–L437.

    CAS  PubMed  Google Scholar 

  32. Jette C., Peterson P.W., Sandoval I.T., Manos E.J., Hadley E., Ireland C.M., Jones D.A. 2004. The tumor suppressor adenomatous polyposis coli and caudal related homeodomain protein regulate expression of retinol dehydrogenase L. J. Biol. Chem. 279, 34397–34405.

    Article  CAS  PubMed  Google Scholar 

  33. 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, 429–433.

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  35. Zheng W.L., Kuppumbatti Y.S., Rexer B., Jing Y., Ong D.E. 2000. Retinol conversion to retinoic acid is impaired in breast cancer cell lines relative to normal cells. J. Cell Physiol. 185, 302–309.

    Article  PubMed  Google Scholar 

  36. Parés X., Farres J., Kedishvili N., Duester G. 2008. Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism. Cell. Mol. Life Sci. 65, 3936–3949.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Belyaeva O.V., Johnson M.P., Kedishvili N.Y. 2008. Kinetic analysis of human enzyme RDH10 defines the characteristics of a physiologically relevant retinol dehydrogenase. J. Biol. Chem. 283, 20299–20308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Molotkov A., Deltour L., Foglio M.H., Cuenca A.E., 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, 13804–13811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Collins M.D., 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, 652–659.

    Article  CAS  PubMed  Google Scholar 

  40. Yokoyama H., Matsumoto M., Shiraishi H., Miyagi M., Kato A.S., Ishii H. 2001. Nicotinamide adenine dinucleotide-dependent retinoic acid formation from retinol in the human gastric mucosa: Inhibition by ethanol, acetaldehyde, and H2 blockers. Alcohol. Clin. Exp. Res. 25, 24S–28S.

    Article  CAS  PubMed  Google Scholar 

  41. Chase J.R., Poolman M.G., Fell D.A. 2009. Contribution of NADH increases to ethanol’s inhibition of retinol oxidation by human ADH isoforms. Alcohol. Clin. Exp. Res. 33, 571–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sandell L.L., Lynn M.L., Inman K.E., McDowell W., Trainor P.A. 2012. RDH10 oxidation of vitamin A is a critical control step in synthesis of retinoic acid during mouse embryogenesis. PLoS ONE. 7, e30698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Parlesak A., Menzl I., Feuchter A., Bode J.C., Bode C. 2000. Inhibition of retinol oxidation by ethanol in the rat liver and colon. Gut. 47, 825–831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chetyrkin S.V., Belyaeva O.V., Gough W.H., Kedishvili N.Y. 2001. Characterization of a novel type of human microsomal 3a-hydroxysteroid dehydrogenase: Unique tissue distribution and catalytic properties. J. Biol. Chem. 276, 22278–22286.

    Article  CAS  PubMed  Google Scholar 

  45. Molotkov A., Fan X., Deltour L., Foqlio M.N., Martras S., Farrés J., Parrés X., Duster G. 2002. Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proc. Natl. Acad. Sci. U. S. A. 99, 5337–5342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Belyaeva O.V., Korkina O.V., Stetsenko A.V., Kim T., Nelson P.S., Kedishvili N.Y. 2005. Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): Catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids. Biochemistry. 44, 7035–7047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gallego O., Belyaeva O.V., Porté S., Ruiz F.X., Stetsenko A.V., Shabrova E.V., Kostereva N.V., Farrés J., Parés X., Kedishvili N.Y. 2006. Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases/reductases and aldo-keto reductases with retinoids. Biochem. J. 399, 101–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fukomoto S., Yamauchi N., Moriguchi H., Hippo Y., Watanabe A., Shibahara J., Taniguchi H., Ishikawa S., Ito H., Yamamoto S., Iwanari H., Hironaka M., Ishikawa Y., Niki T., Sohara Y., 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, 1776–1785.

    Article  Google Scholar 

  49. Molotkov A., Duester G. 2003. Genetic evidence that retinaldehyde dehydrogenase Raldh1 (Aldh1a1) functions downstream of alcohol dehydrogenase Adh1 in metabolism of retinol to retinoic acid. J. Biol. Chem. 278, 36085–36090.

    Article  CAS  PubMed  Google Scholar 

  50. Ross A.C., Zolfaghari R. 2011. Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu. Rev. Nutr. 31, 65–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li B., Gao M.H., Chu X.M., Teng L., Lv C.Y., Yang P., Yin Q.F. 2015. The synergistic antitumor effects of alltrans retinoic acid and C-phycocyanin on the lung cancer A549 cells in vitro and in vivo. Eur. J. Pharmacol. 749, 107–114.

    Article  CAS  PubMed  Google Scholar 

  52. Chen C.F., Goyette P., Lohnes D. 2004. RARgamma acts as a tumor suppressor in mouse keratinocytes. Oncogene. 23, 5350–5359.

    Article  CAS  PubMed  Google Scholar 

  53. Balasubramanian S., Chandraratna R.A., Eckert R.L. 2004. Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid. Carcinogenesis. 25, 1377–1385.

    Article  CAS  PubMed  Google Scholar 

  54. Khuri F.R., Rigas J.R., Figlin R.A., Gralla R.J., Shin D.M., Munden R., Fox N., Huyghe M.R., Kean Y., Reich S.D., Hong W.K. 2001. Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 19, 2626–2637.

    CAS  PubMed  Google Scholar 

  55. Wan H., Oridate N., Lotan D., Hong W.K., Lotan R. 1999. Overexpression of retinoic acid receptor beta in head and neck squamous cell carcinoma cells increases their sensitivity to retinoid-induced suppression of squamous differentiation by retinoids. Cancer Res. 59, 3518–3526.

    CAS  PubMed  Google Scholar 

  56. Tanaka T., De Luca L.M. 2009. Therapeutic potential of “rexinoids” in cancer prevention and treatment. Cancer Res. 69, 4945–4947.

    Article  CAS  PubMed  Google Scholar 

  57. Herriges M.J., Swarr D.T., Morley M.P., Rathi K.S., Peng T., Stewart K.M., Morrisey E.E. 2014. Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development. Genes Dev. 28, 1363–1379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Garattini E., Bolis M., Garattini S.K., Fratelli M., Centritto F., Paroni G., Gianni M., Zanetti A., Pagani A., Fisher J.N., Zambelli A., Terao M. 2014. Retinoids and breast cancer: From basic studies to the clinic and back again. Cancer Treat. Rev. 40, 739–749.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    E. S. Kuznetsova, O. L. Zinovieva, N. Yu. Oparina, M. M. Prokofjeva, P. V. Spirin, N. A. Lisitsyn, V. S. Prassolov & T. D. Mashkova

  2. Blokhin Cancer Research Center, The Ministry of Health of the Russian Federation, Moscow, 115478, Russia

    I. A. Favorskaya & I. B. Zborovskaya

Authors
  1. E. S. Kuznetsova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O. L. Zinovieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Yu. Oparina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. M. Prokofjeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. V. Spirin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I. A. Favorskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I. B. Zborovskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N. A. Lisitsyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. V. S. Prassolov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T. D. Mashkova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. D. Mashkova.

Additional information

Original Russian Text © E.S. Kuznetsova, O.L. Zinovieva, N.Yu. Oparina, M.M. Prokofjeva, P.V. Spirin, I.A. Favorskaya, I.B. Zborovskaya, N.A. Lisitsyn, V.S. Prassolov, T.D. Mashkova, 2016, published in Molekulyarnaya Biologiya, 2016, Vol. 50, No. 2, pp. 255–265.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kuznetsova, E.S., Zinovieva, O.L., Oparina, N.Y. et al. Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer. Mol Biol 50, 220–229 (2016). https://doi.org/10.1134/S0026893316020138

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893316020138

Keywords

Search

Navigation