Skip to main content
Log in

Correlated downregulation of VDR and CYP3A4 in colorectal cancer

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

The evidence obtained from experimental studies suggests the tumor-suppressive effects of vitamin D by controlling the differentiation, proliferation, and apoptosis in cancerous cells. Furthermore, the deregulation of genes involved in vitamin D metabolism has been reported in several types of cancer.

Methods

In the present study, we investigated the expression level of vitamin D metabolic pathway genes, including VDR, CYP3A4, RXRα, and GC, in colorectal cancer (CRC) samples compared with the adjacent tissues by using quantitative RT-PCR.

Results

The results indicated significant downregulation of CYP3A4 and VDR genes in CRC tissues compared with the adjacent control tissues (p < 0.01). RXRA and GC expression levels did not show any significant alteration among the studied samples. Moreover, a positive correlation was observed between the expression level of CYP3A4 and VDR genes (p < 0.0001). ROC curve analysis also revealed the potential diagnostic power of CYP3A4 and VDR genes in CRC samples.

Conclusion

Reduction in the expression of both CYP3A4 and VDR plays an important role in CRC due to the possible impairment in vitamin D metabolism. Further studies concerning the relationship between the expression of these genes and colorectal cancer pathogenesis and treatment are recommended.

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
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The data supporting this study's findings are available from the corresponding author upon reasonable request.

References

  1. Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE (2021) A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers 13(9):2025

    Article  CAS  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 71(3):209–249

    Google Scholar 

  3. Rawla P, Sunkara T, Barsouk A (2019) Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Przeglad Gastroenterologiczny 14(2):89

    CAS  Google Scholar 

  4. Dolatkhah R, Somi MH, Bonyadi MJ, Asvadi Kermani I, Farassati F, Dastgiri S (2015) Colorectal cancer in Iran: molecular epidemiology and screening strategies. J Cancer Epidemiol 2015:1–10

    Article  Google Scholar 

  5. Hong SN (2018) Genetic and epigenetic alterations of colorectal cancer. Intest Res 16(3):327–337. https://doi.org/10.5217/ir.2018.16.3.327

    Article  Google Scholar 

  6. Jeon S-M, Shin E (2018) Exploring vitamin D metabolism and function in cancer. Exp Mol Med 50(4):1–14

    Google Scholar 

  7. Boughanem H, Canudas S, Hernandez-Alonso P, Becerra-Tomás N, Babio N, Salas-Salvadó J et al (2021) Vitamin D intake and the risk of colorectal cancer: an updated meta-analysis and systematic review of case-control and prospective cohort studies. Cancers 13(11):2814

    Article  CAS  Google Scholar 

  8. Sadeghi H, Kamaliyan Z, Mohseni R, Sahebi U, Nazemalhosseini-Mojarad E, Aghaei N et al (2021) Dysregulation of vitamin D synthesis pathway genes in colorectal cancer: a case-control study. J Clin Lab Anal 35(2):e23617

    Article  CAS  Google Scholar 

  9. Afshan FU, Masood A, Nissar B, Chowdri NA, Naykoo NA, Majid M et al (2021) Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer-A study from Kashmir valley. Cancer Genet 252–253:96–106. https://doi.org/10.1016/j.cancergen.2021.01.002

    Article  CAS  Google Scholar 

  10. Sadeghi H, Nazemalhosseini-Mojarad E, Sahebi U, Fazeli E, Azizi-Tabesh G, Yassaee VR et al (2021) Novel long noncoding RNAs upregulation may have synergistic effects on the CYP24A1 and PFDN4 biomarker role in human colorectal cancer. J Cell Physiol 236(3):2051–2057

    Article  CAS  Google Scholar 

  11. Sun H, Wang C, Hao M, Sun R, Wang Y, Liu T et al (2016) CYP24A1 is a potential biomarker for the progression and prognosis of human colorectal cancer. Hum Pathol 50:101–108. https://doi.org/10.1016/j.humpath.2015.11.008

    Article  CAS  Google Scholar 

  12. Yi C, Huang C, Wang H, Wang C, Dong L, Gu X et al (2020) Association study between CYP24A1 gene polymorphisms and cancer risk. Pathol Res Pract 216(1):152735. https://doi.org/10.1016/j.prp.2019.152735

    Article  CAS  Google Scholar 

  13. Egan JB, Thompson PA, Ashbeck EL, Conti DV, Duggan D, Hibler E et al (2010) Genetic polymorphisms in vitamin D receptor VDR/RXRA influence the likelihood of colon adenoma recurrence. Can Res 70(4):1496–1504

    Article  CAS  Google Scholar 

  14. Huang G-L, Chen Q-X, Ma J-J, Sui S-Y, Wang Y-N, Shen D-Y (2019) Retinoic acid receptor α facilitates human colorectal cancer progression via Akt and MMP2 signaling. Onco Targets Ther 12:3087

    Article  CAS  Google Scholar 

  15. van Eijk M, Boosman RJ, Schinkel AH, Huitema ADR, Beijnen JH (2019) Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes. Cancer Chemother Pharmacol 84(3):487–499

    Article  Google Scholar 

  16. Wang Z, Schuetz EG, Xu Y, Thummel KE (2013) Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol 136:54–58

    Article  CAS  Google Scholar 

  17. Bouillon R, Schuit F, Antonio L, Rastinejad F (2020) Vitamin D binding protein: a historic overview. Front Endocrinol 10:910

    Article  Google Scholar 

  18. Anic GM, Weinstein SJ, Mondul AM, Männistö S, Albanes D (2014) Serum vitamin D, vitamin D binding protein, and risk of colorectal cancer. PLoS ONE 9(7):e102966

    Article  Google Scholar 

  19. Poynter JN, Jacobs ET, Figueiredo JC, Lee WH, Conti DV, Campbell PT et al (2010) Genetic variation in the vitamin D receptor (VDR) and the vitamin D–binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry. Cancer Epidemiol Prev Biomark 19(2):525–536

    Article  CAS  Google Scholar 

  20. Li Z, Jia Z, Gao Y, Xie D, Wei D, Cui J et al (2015) Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness. Clin Cancer Res 21(4):844–853

    Article  CAS  Google Scholar 

  21. Sana S, Kayani MA (2021) Role of Vitamin D deficiency and mRNA expression of VDR and RXR in haematological cancers. Mol Biol Rep 48(5):4431–4439

    Article  CAS  Google Scholar 

  22. Evans S, Nolla J, Hanfelt J, Shabahang M, Nauta RJ, Shchepotin IB (1998) Vitamin D receptor expression as a predictive marker of biological behavior in human colorectal cancer. Clin Cancer Res 4(7):1591–1595

    CAS  Google Scholar 

  23. Saccone D, Asani F, Bornman L (2015) Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene 561(2):171–180

    Article  CAS  Google Scholar 

  24. Thomas M, Sylvester P, Newcomb P, Longman R (1999) Vitamin D receptor expression in colorectal cancer. J Clin Pathol 52(3):181–183

    Article  CAS  Google Scholar 

  25. Kacevska M, Robertson GR, Clarke SJ, Liddle C (2008) Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol 4(2):137–149

    Article  CAS  Google Scholar 

  26. Gervasini G, García-Martín E, Ladero JM, Pizarro R, Sastre J, Martínez C et al (2007) Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients. BMC Cancer 7(1):1–7

    Article  Google Scholar 

  27. Kumarakulasingham M, Rooney PH, Dundas SR, Telfer C, Melvin WT, Curran S et al (2005) Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis. Clin Cancer Res 11(10):3758–3765

    Article  CAS  Google Scholar 

  28. Dhaini HR, Thomas DG, Giordano TJ, Johnson TD, Biermann JS, Leu K et al (2003) Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma. J Clin Oncol 21(13):2481–2485

    Article  CAS  Google Scholar 

  29. Pavek P, Pospechova K, Svecova L, Syrova Z, Stejskalova L, Blazkova J et al (2010) Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene. Biochem Pharmacol 79(2):277–287

    Article  CAS  Google Scholar 

  30. Roizen JD, Li D, O’Lear L, Javaid MK, Shaw NJ, Ebeling PR et al (2018) CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Investig 128(5):1913–1918

    Article  Google Scholar 

  31. Andersen SW, Shu XO, Cai Q, Khankari NK, Steinwandel MD, Jurutka PW et al (2017) Total and free circulating vitamin D and vitamin D-binding protein in relation to colorectal cancer risk in a prospective study of African Americans. Cancer Epidemiol Biomark Prev 26(8):1242–1247

    Article  CAS  Google Scholar 

  32. Gibbs DC, Bostick RM, McCullough ML, Um CY, Flanders WD, Jenab M et al (2020) Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common, inherited vitamin D-binding protein isoforms. Int J Cancer 147(10):2725–2734

    Article  CAS  Google Scholar 

  33. Zhang F, Meng F, Li H, Dong Y, Yang W, Han A (2011) Suppression of retinoid X receptor alpha and aberrant β-catenin expression significantly associates with progression of colorectal carcinoma. Eur J Cancer (Oxf, Engl: 1990). 47(13):2060–2067

    Article  CAS  Google Scholar 

  34. Wasiewicz T, Piotrowska A, Wierzbicka J (2018) Antiproliferative activity of non-calcemic vitamin D analogs on human melanoma lines in relation to VDR and PDIA3 receptors. Int J Mol Sci 19(9):2583

    Article  Google Scholar 

  35. Ozawa S, Miura T, Terashima J, Habano W (2021) Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review. Cancer Drug Resist (Alhambra, Calif) 4(4):946–964

    CAS  Google Scholar 

  36. Nallani SC, Goodwin B, Buckley AR, Buckley DJ, Desai PB (2004) Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs, docetaxel and paclitaxel, assessed employing primary human hepatocytes. Cancer Chemother Pharmacol 54(3):219–229

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was financially supported by the Research Department of the School of Medicine, Shahid Beheshti University of Medical Sciences (Pajoohan code: 26158).

Funding

The study was financially supported by the “Research Department of the School of Medicine, Shahid Beheshti University of Medical Sciences” (Pajoohan code: 26158).

Author information

Authors and Affiliations

Authors

Contributions

HS, and RM contributed to the study conception and design. Material preparation, data collection and analysis were performed by ENM and MRG. HS wrote the first draft of the manuscript. RM and VH revised the final version of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Reza Mirfakhraie.

Ethics declarations

Conflict of interest

The authors report no conflict of interest associated with this manuscript.

Ethical approval

This research was conducted in compliance with the ethical principles of the Helsinki Declaration and under the protocols of the Ethics Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.MSP.REC.1400.141).

Informed consent

Informed consent was taken from all the patients who participated in this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sadeghi, H., Hashemnia, V., Nazemalhosseini-Mojarad, E. et al. Correlated downregulation of VDR and CYP3A4 in colorectal cancer. Mol Biol Rep 50, 1385–1391 (2023). https://doi.org/10.1007/s11033-022-08141-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-08141-2

Keywords

Navigation