Skip to main content


Log in

Expression and clinical significance of CRABP1 and CRABP2 in non-small cell lung cancer

  • Research Article
  • Published:
Tumor Biology


The impairment of retinoic acid (RA)-dependent signaling is a frequent event during carcinogenesis. Cellular retinoic acid-binding proteins (CRABP1 and CRABP2) are important modulators of RA activity. Up to date, the role of these proteins in cancer progression remains poorly investigated. Here, we studied for the first time the simultaneous messenger RNA (mRNA) and protein expression of CRABPs in non-small cell lung cancer (NSCLC) samples. CRABP1 and CRABP2 mRNA levels were elevated in 42 and 56 % of NSCLC samples, respectively. Decrease of CRABP2 mRNA expression was significantly associated with the presence of lymph node metastases. Protein expression of CRABP1 and CRABP2 was detected in 50 and 56 % of tumor samples, respectively. We also found a positive correlation between CRABP1 and CRABP2 expression. Taken together, we demonstrated significant changes in CRABP expression in NSCLC samples. Importantly, the presented data provide the first evidence of potential involvement of CRABP2 in lung cancer metastasis.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others


  1. Bushue N, Wan YJ. Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev. 2010;62(13):1285–98. doi:10.1016/j.addr.2010.07.003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Theodosiou M, Laudet V, Schubert M. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell Mol Life Sci CMLS. 2010;67(9):1423–45. doi:10.1007/s00018-010-0268-z.

    Article  CAS  PubMed  Google Scholar 

  3. Dong D, Ruuska SE, Levinthal DJ, Noy N. Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid. J Biol Chem. 1999;274(34):23695–8.

    Article  CAS  PubMed  Google Scholar 

  4. Budhu AS, Noy N. Direct channeling of retinoic acid between cellular retinoic acid-binding protein II and retinoic acid receptor sensitizes mammary carcinoma cells to retinoic acid-induced growth arrest. Mol Cell Biol. 2002;22(8):2632–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Ross AC. Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins. FASEB J Off Publ Fed Am Soc Exp Biol. 1993;7(2):317–27.

    CAS  Google Scholar 

  6. Won JY, Nam EC, Yoo SJ, Kwon HJ, Um SJ, Han HS, et al. The effect of cellular retinoic acid binding protein-I expression on the CYP26-mediated catabolism of all-trans retinoic acid and cell proliferation in head and neck squamous cell carcinoma. Metab Clin Exp. 2004;53(8):1007–12.

    Article  CAS  PubMed  Google Scholar 

  7. Napoli JL. Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1999;1440(2–3):139–62.

    Article  CAS  PubMed  Google Scholar 

  8. Fiorella PD, Napoli JL. Expression of cellular retinoic acid binding protein (CRABP) in Escherichia coli. Characterization and evidence that holo-CRABP is a substrate in retinoic acid metabolism. J Biol Chem. 1991;266(25):16572–9.

    CAS  PubMed  Google Scholar 

  9. Tang XH, Vivero M, Gudas LJ. Overexpression of CRABPI in suprabasal keratinocytes enhances the proliferation of epidermal basal keratinocytes in mouse skin topically treated with all-trans retinoic acid. Exp Cell Res. 2008;314(1):38–51. doi:10.1016/j.yexcr.2007.07.016.

    Article  CAS  PubMed  Google Scholar 

  10. Tanaka K, Imoto I, Inoue J, Kozaki K, Tsuda H, Shimada Y, et al. Frequent methylation-associated silencing of a candidate tumor-suppressor, CRABP1, in esophageal squamous-cell carcinoma. Oncogene. 2007;26(44):6456–68. doi:10.1038/sj.onc.1210459.

    Article  CAS  PubMed  Google Scholar 

  11. Lee HS, Kim BH, Cho NY, Yoo EJ, Choi M, Shin SH, et al. Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(3):812–20. doi:10.1158/1078-0432.CCR-08-0266.

    Article  CAS  Google Scholar 

  12. Calmon MF, Rodrigues RV, Kaneto CM, Moura RP, Silva SD, Mota LD, et al. Epigenetic silencing of CRABP2 and MX1 in head and neck tumors. Neoplasia. 2009;11(12):1329–39.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Geiger T, Madden SF, Gallagher WM, Cox J, Mann M. Proteomic portrait of human breast cancer progression identifies novel prognostic markers. Cancer Res. 2012;72(9):2428–39. doi:10.1158/0008-5472.CAN-11-3711.

    Article  CAS  PubMed  Google Scholar 

  14. Ramakers C, Ruijter JM, Deprez RH, Moorman AF. Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett. 2003;339(1):62–6.

    Article  CAS  PubMed  Google Scholar 

  15. Osanai M, Sawada N, Lee GH. Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1. Oncogene. 2010;29(8):1135–44. doi:10.1038/onc.2009.414.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Z, Joh K, Yatsuki H, Zhao W, Soejima H, Higashimoto K, et al. Retinoic acid receptor beta2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells. Cancer Lett. 2007;247(2):318–27. doi:10.1016/j.canlet.2006.05.013.

    Article  CAS  PubMed  Google Scholar 

  17. Campos B, Centner FS, Bermejo JL, Ali R, Dorsch K, Wan F, et al. Aberrant expression of retinoic acid signaling molecules influences patient survival in astrocytic gliomas. Am J Pathol. 2011;178(5):1953–64. doi:10.1016/j.ajpath.2011.01.051.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Miyake T, Ueda Y, Matsuzaki S, Miyatake T, Yoshino K, Fujita M, et al. CRABP1-reduced expression is associated with poorer prognosis in serous and clear cell ovarian adenocarcinoma. J Cancer Res Clin Oncol. 2011;137(4):715–22. doi:10.1007/s00432-010-0930-8.

    Article  CAS  PubMed  Google Scholar 

  19. Siddiqui NA, Thomas EJ, Dunlop W, Redfern CP. Retinoic acid receptors and retinoid binding proteins in endometrial adenocarcinoma: differential expression of cellular retinoid binding proteins in endometrioid tumours. Int J Cancer (J Int Cancer). 1995;64(4):253–63.

    Article  CAS  Google Scholar 

  20. Jin BY, Fu GH, Jiang X, Pan H, Zhou DK, Wei XY, et al. CRABP2 and FABP5 identified by 2D DIGE profiling are upregulated in human bladder cancer. Chin Med J. 2013;126(19):3787–9.

    PubMed  Google Scholar 

  21. Banz C, Ungethuem U, Kuban RJ, Diedrich K, Lengyel E, Hornung D. The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer. Fertil Steril. 2010;94(4):1212–7. doi:10.1016/j.fertnstert.2009.06.039.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Kainov Y, Favorskaya I, Delektorskaya V, Chemeris G, Komelkov A, Zhuravskaya A et al. CRABP1 provides high malignancy of transformed mesenchymal cells and contributes to the pathogenesis of mesenchymal and neuroendocrine tumors. Cell Cycle. 2014;13(10).

  23. Lind GE, Kleivi K, Meling GI, Teixeira MR, Thiis-Evensen E, Rognum TO, et al. ADAMTS1, CRABP1, and NR3C1 identified as epigenetically deregulated genes in colorectal tumorigenesis. Cell Oncol Off J Int Soc Cell Oncol. 2006;28(5–6):259–72.

    CAS  Google Scholar 

  24. Huang Y, de la Chapelle A, Pellegata NS. Hypermethylation, but not LOH, is associated with the low expression of MT1G and CRABP1 in papillary thyroid carcinoma. Int J Cancer (J Int Cancer). 2003;104(6):735–44. doi:10.1002/ijc.11006.

    Article  CAS  Google Scholar 

  25. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell. 2007;129(4):723–33. doi:10.1016/j.cell.2007.02.050.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Vreeland AC, Yu S, Levi L, de Barros Rossetto D, Noy N. Transcript stabilization by the RNA-binding protein HuR is regulated by cellular retinoic acid-binding protein 2. Mol Cell Biol. 2014;34(12):2135–46. doi:10.1128/MCB.00281-14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Jing Y, Waxman S, Mira-y-Lopez R. The cellular retinoic acid binding protein II is a positive regulator of retinoic acid signaling in breast cancer cells. Cancer Res. 1997;57(9):1668–72.

    CAS  PubMed  Google Scholar 

  28. Pfoertner S, Goelden U, Hansen W, Toepfer T, Geffers R, Ukena SN, et al. Cellular retinoic acid binding protein I: expression and functional influence in renal cell carcinoma. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2005;26(6):313–23. doi:10.1159/000089262.

    Article  CAS  Google Scholar 

  29. Blaese MA, Santo-Hoeltje L, Rodemann HP. CRABP I expression and the mediation of the sensitivity of human tumour cells to retinoic acid and irradiation. Int J Radiat Biol. 2003;79(12):981–91. doi:10.1080/09553000310001632949.

    Article  CAS  PubMed  Google Scholar 

  30. Gupta S, Pramanik D, Mukherjee R, Campbell NR, Elumalai S, de Wilde RF, et al. Molecular determinants of retinoic acid sensitivity in pancreatic cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(1):280–9. doi:10.1158/1078-0432.CCR-11-2165.

    Article  CAS  Google Scholar 

Download references


This study was supported by the Russian Foundation of Basic Research (grants 14-04-31744 MOL_A_2014 and 14-04-01706-а) and Russian Science Foundation for N. N. Blokhin Russian Cancer Research Center, Moscow, Russia. The study sponsors have not been involved in the study design, collection, analysis, and interpretation of data or others.

Conflicts of interest


Author information

Authors and Affiliations


Corresponding author

Correspondence to Irina Favorskaya.

Additional information

Irina Zborovskaya and Elena Tchevkina, senior authors, contributed equally to the work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

(DOCX 12 kb)

Supplementary Table 2

(DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Favorskaya, I., Kainov, Y., Chemeris, G. et al. Expression and clinical significance of CRABP1 and CRABP2 in non-small cell lung cancer. Tumor Biol. 35, 10295–10300 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: