Skip to main content
SpringerLink
Log in

The evaluation of chitosan hydrogel based curcumin effect on DNMT1, DNMT3A, DNMT3B, MEG3, HOTAIR gene expression in glioblastoma cell line

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

Abstract

Background

Cancer is one of the most important causes of death worldwide. Some types of cancer, including glioblastoma, with a high potential for growth, invasion, and resistance to general treatments, chemotherapy, and radiotherapy, have a high potential for recurrence. Many chemical drugs have been used to treat it, but herbal drugs are more effective with fewer side effects; Therefore, this research aims to investigate the effect of curcumin-chitosan nano-complex on the expression of MEG3, HOTAIR, DNMT1, DNMT3A, DNMT3B genes in the glioblastoma cell line.

Methods

In this research, glioblastoma cell line, PCR and spectrophotometry techniques, MTT test and transmission, field emission transmission, and fluorescent electron microscopes were used.

Results

The morphological examination of the curcumin-chitosan nano-complex was without clumping, and the fluorescent microscope examination showed the nano-complex enters the cell and affects the genes expression. In its bioavailability studies, it was found that it significantly increases the death of cancer cells in a dose- and time-dependent manner. Gene expression tests showed that this nano-complex increased MEG3 gene expression compared to the control group, which is statistically significant (p < 0.05). It also decreased HOTAIR gene expression compared to the control group, which was not statistically significant (p > 0.05). It decreased the expression of DNMT1, DNMT3A, and DNMT3B genes compared to the control group, which is statistically significant (p < 0.05).

Conclusion

By using active plant substances such as curcumin, the active demethylation of brain cells can be directed to the path of inhibiting the growth of brain cancer cells and eliminating them.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets generated or analyzed during the current study are available from the corresponding author upon resealable request.

Code availability

Not applicable.

Abbreviations

MEG3:

Maternally expressed 3

HOTAIR:

HOX transcript antisense RNA

DNMT1:

DNA (cytosine-5)-methyltransferase 1

DNMT3A:

DNA (cytosine-5)-methyltransferase 3A

DNMT3B:

DNA (cytosine-5)-methyltransferase 3B

References

  1. Cao Y, DePinho RA, Ernst M, Vousden K (2011) Cancer research: past, present and future. Nat Rev Cancer 11(10):749–754. https://doi.org/10.1038/nrc3138

    Article  CAS  PubMed  Google Scholar 

  2. Holland EC (2000) Glioblastoma multiforme: the terminator. Proc Natl Acad Sci 97(12):6242–6244. https://doi.org/10.1073/pnas.97.12.6242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dell’Albani P (2008) Stem cell markers in gliomas. Neurochem Res 33(12):2407–2415

    Article  PubMed  Google Scholar 

  4. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428. https://doi.org/10.1007/s11064-008-9723-8

    Article  CAS  PubMed  Google Scholar 

  5. Feingold EA, Pachter L (2004) The encode (ENCyclopedia of DNA elements) project. Science 306(5696):636–640. https://doi.org/10.1126/science.1105136

    Article  CAS  Google Scholar 

  6. Amaral PP, Mattick JS (2008) Noncoding RNA in development. Mamm Genome 19(7):454–492

    Article  CAS  PubMed  Google Scholar 

  7. Mehler MF, Mattick JS (2007) Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease. Physiol Rev 87(3):799–823. https://doi.org/10.1152/physrev.00036.2006

    Article  CAS  PubMed  Google Scholar 

  8. Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY, Becker-Santos DD, MacAulay CE, Lam S, Brown CJ, Lam WL (2011) Human cancer long non-coding RNA transcriptomes. PLoS ONE 6(10):e25915. https://doi.org/10.1371/journal.pone.0025915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Louro R, Smirnova AS, Verjovski-Almeida S (2009) Long intronic noncoding RNA transcription: expression noise or expression choice? Genomics 93(4):291–298. https://doi.org/10.1016/j.ygeno.2008.11.009

    Article  CAS  PubMed  Google Scholar 

  10. Bender CM, Zingg JM, Jones PA (1998) DNA methylation as a target for drug design. Pharm Res 15(2):175–187. https://doi.org/10.1023/A:1011946030404

    Article  CAS  PubMed  Google Scholar 

  11. Santini V, Kantarjian HM, Issa JP (2001) Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med 134(7):573–586. https://doi.org/10.7326/0003-4819-134-7-200104030-00011

    Article  CAS  PubMed  Google Scholar 

  12. Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, Klibanski A (2003) A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab 88(11):5119–5126. https://doi.org/10.1210/jc.2003-030222

    Article  CAS  PubMed  Google Scholar 

  13. Zhang X, Rice K, Wang Y, Chen W, Zhong Y, Nakayama Y, Zhou Y, Klibanski A (2010) Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151(3):939–947. https://doi.org/10.1210/en.2009-0657

    Article  CAS  PubMed  Google Scholar 

  14. Xiao Xu et al (2022) The role of insulin-like growth factor 2 mRNA binding proteins in female reproductive pathophysiology. Reprod Biol Endocrinol 20(1):1–12. https://doi.org/10.1186/s12958-022-00960-z

    Article  CAS  Google Scholar 

  15. Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, Ansell PJ, Zhao J, Weng C, Klibanski A (2007) Activation of p53 by MEG3 non-coding RNA. J Biol Chem 282(34):24731–24742. https://doi.org/10.1074/jbc.M702029200

    Article  CAS  PubMed  Google Scholar 

  16. Lim JH, Park JW, Min DS, Chang JS, Lee YH, Park YB, Choi KS, Kwon TK (2007) NAG-1 up-regulation mediated by EGR-1 and p53 is critical for quercetin-induced apoptosis in HCT116 colon carcinoma cells. Apoptosis 12(2):411–421. https://doi.org/10.1007/s10495-006-0576-9

    Article  CAS  PubMed  Google Scholar 

  17. Benetatos L, Dasoula A, Hatzimichael E, Georgiou I, Syrrou M, Bourantas KL (2008) Promoter hypermethylation of the MEG3 (DLK1/MEG3) imprinted gene in multiple myeloma. Clin Lymphoma Myeloma 8(3):171–175. https://doi.org/10.3816/CLM.2008.n.021

    Article  CAS  PubMed  Google Scholar 

  18. Benetatos L, Vartholomatos G, Hatzimichael E (2011) MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer 129(4):773–779. https://doi.org/10.1002/ijc.26052

    Article  CAS  PubMed  Google Scholar 

  19. Aggarwal BB, Harikumar KB (2009) Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 41(1):40–59. https://doi.org/10.1016/j.biocel.2008.06.010

    Article  CAS  PubMed  Google Scholar 

  20. Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 75(4):787–809. https://doi.org/10.1016/j.bcp.2007.08.016

    Article  CAS  PubMed  Google Scholar 

  21. Karavasili C, Panteris E, Vizirianakis IS, Koutsopoulos S, Fatouros DG (2018) Chemotherapeutic delivery from a self-assembling peptide nanofiber hydrogel for the management of glioblastoma. Pharm Res 35(8):1–3. https://doi.org/10.1007/s11095-018-2442-1

    Article  CAS  Google Scholar 

  22. Wong SC, Kamarudin MN, Naidu R (2021) Anticancer mechanism of curcumin on human glioblastoma. Nutrients 13(3):950. https://doi.org/10.3390/nu13030950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Walker BC, Mittal S (2020) Antitumor activity of curcumin in glioblastoma. Int J Mol Sci 21(24):9435. https://doi.org/10.3390/ijms21249435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M (2016) Curcumin and health. Molecules 21(3):264. https://doi.org/10.3390/molecules21030264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Do NH, Truong QT, Le PK, Ha AC (2022) Recent developments in chitosan hydrogels carrying natural bioactive compounds. Carbohydr Polym 14:119726. https://doi.org/10.1016/j.carbpol.2022.119726

    Article  CAS  Google Scholar 

  26. Pishavar E, Khosravi F, Naserifar M, Rezvani Ghomi E, Luo H, Zavan B, Seifalian A, Ramakrishna S (2021) Multifunctional and self-healable intelligent hydrogels for cancer drug delivery and promoting tissue regeneration in vivo. Polymers 13(16):2680. https://doi.org/10.3390/polym13162680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mu M, Li X, Tong A, Guo G (2019) Multi-functional chitosan-based smart hydrogels mediated biomedical application. Expert Opin Drug Deliv 16(3):239–250. https://doi.org/10.1080/17425247.2019.1580691

    Article  CAS  PubMed  Google Scholar 

  28. Doello K, Ortiz R, Alvarez PJ, Melguizo C, Cabeza L, Prados J (2018) Latest in vitro and in vivo assay, clinical trials and patents in cancer treatment using curcumin: a literature review. Nutr Cancer 70(4):569–578. https://doi.org/10.1080/01635581.2018.1464347

    Article  CAS  PubMed  Google Scholar 

  29. Giordano A, Tommonaro G (2019) Curcumin and cancer. Nutrients 11(10):2376. https://doi.org/10.3390/nu11102376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weng W, Goel A (2020) Curcumin and colorectal cancer: an update and current perspective on this natural medicine. Seminars in cancer biology. Academic Press, Cambridge

    Google Scholar 

  31. Farghadani R, Naidu R (2021) Curcumin: modulator of key molecular signaling pathways in hormone-independent breast cancer. Cancers (Basel) 13(14):3427. https://doi.org/10.3390/cancers13143427

    Article  CAS  PubMed  Google Scholar 

  32. Cao X, Li Y, Wang Y, Yu T, Zhu C, Zhang X, Guan J (2022) Curcumin suppresses tumorigenesis by ferroptosis in breast cancer. PLoS ONE 17(1):e0261370. https://doi.org/10.1371/journal.pone.0261370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pricci M, Girardi B, Giorgio F, Losurdo G, Ierardi E, Di Leo A (2020) Curcumin and colorectal cancer: from basic to clinical evidences. Int J Mol Sci 21(7):2364. https://doi.org/10.3390/ijms21072364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ashrafizadeh M, Najafi M, Makvandi P, Zarrabi A, Farkhondeh T, Samarghandian S (2020) Versatile role of curcumin and its derivatives in lung cancer therapy. J Cell Physiol 235(12):9241–9268. https://doi.org/10.2174/1574892815999201102214602

    Article  CAS  PubMed  Google Scholar 

  35. Mohammadi E, Behnam B, Mohammadinejad R, Guest PC, Simental-Mendía LE, Sahebkar A (2021) Antidiabetic properties of curcumin: insights on new mechanisms. Adv Exp Med Biol 1291:151–164

    Article  CAS  PubMed  Google Scholar 

  36. Calaf GM, Ponce-Cusi R, Carrión F (2018) Curcumin and paclitaxel induce cell death in breast cancer cell lines. Oncol Rep 40(4):2381–2388. https://doi.org/10.3892/or.2018.6603

    Article  CAS  PubMed  Google Scholar 

  37. Shahcheraghi SH, Zangui M, Lotfi M, Ghayour-Mobarhan M, Ghorbani A, Jaliani HZ, Sadeghnia HR, Sahebkar A (2019) Therapeutic potential of curcumin in the treatment of glioblastoma multiforme. Curr Pharm Des 25(3):333–342. https://doi.org/10.2174/1381612825666190313123704

    Article  CAS  PubMed  Google Scholar 

  38. Hesari A, Rezaei M, Rezaei M, Dashtiahangar M, Fathi M, Rad JG, Momeni F, Avan A, Ghasemi F (2019) Effect of curcumin on glioblastoma cells. J Cell Physiol 234(7):10281–10288. https://doi.org/10.1002/jcp.27933

    Article  CAS  PubMed  Google Scholar 

  39. Wong KE, Ngai SC, Chan KG, Lee LH, Goh BH, Chuah LH (2019) Curcumin nanoformulations for colorectal cancer: a review. Front Pharmacol 5(10):152. https://doi.org/10.3389/fphar.2019.00152

    Article  CAS  Google Scholar 

  40. Gimple RC, Bhargava S, Dixit D, Rich JN (2019) Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer. Genes Dev 33(11–12):591–609. https://doi.org/10.3389/fphar.2019.00152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shabani M, Mohammad Ganji S, Salahshouri FI (2020) Investigation of long noncoding RNA HOX A11-AS expression in Iranian patients with glioblastoma: a quantitative study. Qom Univ Med Sci J 14(5):22–29. https://doi.org/10.29252/qums.14.5.22

    Article  Google Scholar 

  42. Lakomy R, Kazda T, Selingerova I, Poprach A, Pospisil P, Belanova R, Fadrus P, Vybihal V, Smrcka M, Jancalek R, Hynkova L (2020) Real-world evidence in glioblastoma: stupp’s regimen after a decade. Front Oncol 3(10):840. https://doi.org/10.3389/fonc.2020.00840

    Article  Google Scholar 

  43. Pirmoradi L, Seyfizadeh N, Ghavami S, Zeki AA, Shojaei S (2019) Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy. J Investig Med 67(4):715–719. https://doi.org/10.1136/jim-2018-000962

    Article  PubMed  Google Scholar 

  44. Mirzababaeiy SA, Mahmoudi M, Mohabat R (2018) Fabrication and characterization of hydrogel containing curcumin loaded in chitosan nanoparticles as a new wound dressing. Adv Mater Technol 7(1):53–63. https://doi.org/10.30501/jamt.2018.91681

    Article  Google Scholar 

  45. Parameswari AR, Rajalakshmi G, Kumaradhas P (2015) A combined molecular docking and charge density analysis is a new approach for medicinal research to understand drug–receptor interaction: curcumin–AChE model. Chem Biol Interact 5(225):21–31. https://doi.org/10.1016/j.cbi.2014.09.011

    Article  CAS  Google Scholar 

  46. Ryskalin L, Biagioni F, Busceti CL, Lazzeri G, Frati A, Fornai F (2020) The multi-faceted effect of curcumin in glioblastoma from rescuing cell clearance to autophagy-independent effects. Molecules 25(20):4839. https://doi.org/10.3390/molecules25204839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Trotta T, Panaro MA, Prifti E, Porro C (2019) Modulation of biological activities in glioblastoma mediated by curcumin. Nutr Cancer 71(8):1241–1253. https://doi.org/10.1080/01635581.2019.1604978

    Article  CAS  PubMed  Google Scholar 

  48. Purkayastha S, Berliner A, Fernando SS, Ranasinghe B, Ray I, Tariq H, Banerjee P (2009) Curcumin blocks brain tumor formation. Brain Res 17(1266):130–138. https://doi.org/10.1016/j.brainres.2009.01.066

    Article  CAS  Google Scholar 

  49. Zhang J, Yang C, Wu C, Cui W, Wang L (2020) DNA methyltransferases in cancer: biology, paradox, aberrations, and targeted therapy. Cancers 12(8):2123. https://doi.org/10.3390/cancers12082123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu P, Yang F, Zhang L, Hu Y, Chen B, Wang J, Su L, Wu M, Chen W (2022) Emerging role of different DNA methyltransferases in the pathogenesis of cancer. Front Pharmacol 13:958146. https://doi.org/10.3389/fphar.2022.958146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li Z, Ma Y, Wang G, Wang H, Dai Y, Zhu Y, Chen S, Zheng X, Sun F (2020) Overexpression of human-derived DNMT3A induced intergenerational inheritance of DNA methylation and gene expression variations in rat brain and testis. Epigenetics 15(10):1107–1120. https://doi.org/10.1080/15592294.2020.1749962

    Article  PubMed  PubMed Central  Google Scholar 

  52. Maugeri A, Mazzone MG, Giuliano F, Vinciguerra M, Basile G, Barchitta M, Agodi A (2018) Curcumin modulates DNA methyltransferase functions in a cellular model of diabetic retinopathy. Oxid Med Cell Longev 2018:5407482. https://doi.org/10.1155/2018/5407482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, Yang C (2019) Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet 10:514. https://doi.org/10.3389/fgene.2019.00514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ming T, Tao Q, Tang S, Zhao H, Yang H, Liu M, Ren S, Xu H (2022) Curcumin: an epigenetic regulator and its application in cancer. Biomed Pharmacother 156:113956. https://doi.org/10.1016/j.biopha.2022.113956

    Article  CAS  PubMed  Google Scholar 

  55. Xu J, Wang X, Zhu C, Wang K (2022) A review of current evidence about lncRNA MEG3: A tumor suppressor in multiple cancers. Front Cell Dev Biol 5(10):997633. https://doi.org/10.3389/fcell.2022.997633

    Article  Google Scholar 

  56. Zhang S, Guo W (2019) Long non-coding RNA MEG3 suppresses the growth of glioma cells by regulating the miR-96–5p/MTSS1 signaling pathway. Mol Med Rep 20(5):4215–4225. https://doi.org/10.3892/mmr.2019.10659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gong X, Huang MY (2020) Tumor-suppressive function of lncRNA-MEG3 in glioma cells by regulating miR-6088/SMARCB1 Axis. Biomed Res Int 11(2020):4309161. https://doi.org/10.1155/2020/4309161

    Article  CAS  Google Scholar 

  58. Gao L, Shao T, Zheng W, Ding J (2021) Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer by regulating lncRNA-MEG3 and PTEN signaling. Clin Transl Oncol 23(7):1386–1393. https://doi.org/10.1007/s12094-020-02531-3

    Article  CAS  PubMed  Google Scholar 

  59. Zamani M, Sadeghizadeh M, Behmanesh M (2014) Dendrosomal curcumin upregulates expression of the long non-coding RNA gene MEG3 in U87MG glioblastoma cells. mjms 17(3):41–56

    Google Scholar 

  60. Zamani M, Sadeghizadeh M, Behmanesh M, Najafi F (2015) Dendrosomal curcumin increases expression of the long non-coding RNA gene MEG3 via up-regulation of epi-miRs in hepatocellular cancer. Phytomedicine 22(10):961–967. https://doi.org/10.1016/j.phymed.2015.05.071

    Article  CAS  PubMed  Google Scholar 

  61. Pei CS, Wu HY, Fan FT, Wu Y, Shen CS, Pan LQ (2014) Influence of curcumin on HOTAIR-mediated migration of human renal cell carcinoma cells. Asian Pac J Cancer Prev 15(10):4239–4243. https://doi.org/10.7314/apjcp.2014.15.10.4239

    Article  PubMed  Google Scholar 

  62. Liu JM, Li M, Luo W, Sun HB (2021) Curcumin attenuates Adriamycin-resistance of acute myeloid leukemia by inhibiting the lncRNA HOTAIR/miR-20a-5p/WT1 axis. Lab Invest 101(10):1308–1317. https://doi.org/10.1038/s41374-021-00640-3

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This article is taken from the master’s thesis entitled "Investigation of the effect of curcumin based on hydrogel-chitosan on DNMT1, DNMT3B, DNMT3A, MEG3 and HOTAIR gene expression in glioblastoma cell line" in the Faculty of Basic Sciences, Payame Noor University, Tehran, Shahr-Ray branch. We want to express our gratitude to the Research Vice-Chancellor of Payame Noor University of Shahr-Ray for their support and to all the dear ones who helped us implement this research.

Funding

The authors did not receive any funds, grants or other support from any organization for the submitted work.

Author information

Authors and Affiliations

  1. Department of Biology, Faculty of Sciences, Payame Noor University, Shahre Rey, Iran

    Sanaz Abolfathi

  2. Department of Biology, Faculty of Sciences, Payame Noor University, Tehran, Iran

    Maryam Zare

Authors
  1. Sanaz Abolfathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam Zare
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study’s conception and design. SA and MZ: Designing the study, material preparation, data collection, and analysis were performed. SA: wrote the first draft of the manuscript, and MZ: it was commented, and revised. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Maryam Zare.

Ethics declarations

Conflict of interest

The Authors declare they have no relevant financial or non-financial interests to disclose.

Informed consent

Not applicable.

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

Abolfathi, S., Zare, M. The evaluation of chitosan hydrogel based curcumin effect on DNMT1, DNMT3A, DNMT3B, MEG3, HOTAIR gene expression in glioblastoma cell line. Mol Biol Rep 50, 5977–5989 (2023). https://doi.org/10.1007/s11033-023-08531-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-023-08531-0

Keywords

Search

Navigation