Evaluation of Anticancer and Neuroprotective Properties of Curcumin: a Network Analysis

Document Type : Original paper


1 Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Traditional Medicine and Materia Medica Research Center and Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 Functional Neurosurgery Research Center, Faculty of Medicine Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5 Firoozabadi Hospital, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.

6 Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

7 Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.


Background and objectives: Curcumin as a medicinal substance has shown effective in different kinds of diseases especially cancer. To understand its underlying mechanism, molecular complementary study of differentially expressed microRNAs (DEMs) could assist. In this view, regulatory network analysis of DEMs of melanoma cancer treated with curcumin versus the untreated male Mus musculus was investigated in this study. Methods: Data was obtained from the database of Gene Expression Omnibus (GEO), https://www.ncbi.nlm.nih.gov/geo/.At first, the log fold change (FC)≥ 2 was assigned for predicting a cut off for DEMs in the following study. GEO2R detected a number of 250 top significantly changed microRNAs based on the priority of the most statistically significant ones. These miRNAs were then explored for regulatory network analysis via Cytoscape softwarev.3.7.2 and its plug-ins. Results: The findings indicated that a number of 21 miRNAs were statistically significant with differential expression amounts. Regulatory network also identified important microRNAs of mmu-miR-199a, mmu-miR-199b, mmu-miR-21, mmu-miR-142-3p, mmu-miR-148a, mmu-miR-214 and genes of Pkp3, Usp19, Ercc4, Ttc25, Atp13a2, Akr1b7, Umod, Nup188, Imp3, and Tmem74b. The highest ranked hub was mmu-miR-199a, which had nine connections. Conclusion: The present study offers new insights into the molecular mechanism of curcumin health benefits in melanoma cancer.


Main Subjects

[1] Amalraj A, Pius A, Gopi S, Gopi S. Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives - a review. J Tradit Complement Med. 2017; 7(2): 205-233.
[2] Evance WC. Trease and Evance pharmacognosy. 16th ed. Edinburgh: Elsevier, 2009.
[3] Hewlings SJ, Kalman DS. Curcumin: a review of its’ effects on human health. Foods. 2017; 6(10): 1-11.
[4] Xu XY, Meng X, Li S, Gan RY, Li Y, Li HB. Bioactivity, health benefits, and related molecular mechanisms of curcumin: current progress, challenges, and perspectives. Nutrients. 2018; 10(10): 1-33.
[5] Chen Y, Cao S, Xu P, Han W, Shan T, Pan J, Lin W, Chen X, Wang X. Changes in the expression of miR-34a and its target genes following spinal cord injury in rats. Med Sci Monit. 2016; 22: 3981-3993.
[6] Müller S, Janke F, Dietz S, Sültmann H. Circulating MicroRNAs as potential biomarkers for lung cancer. Recent Results Cancer Res. 2020; 215: 299-318.
[7] Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M. Curcumin and health. Molecules. 2016; 21(3): 1-22.
[8] Slabáková E, Culig Z, Remšík J, Souček K. Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis. 2017; 8(10): 1-10.
[9] Momtazi AA, Shahabipour F, Khatibi S, Johnston TP, Pirro M, Sahebkar A. Curcumin as a MicroRNA regulator in cancer: a review.  Rev Physiol Biochem Pharmacol. 2016; 171: 1-38.
[10] Sekhon K, Bucay N, Majid S, Dahiya R, Saini S. MicroRNAs and epithelial-mesenchymal transition in prostate cancer. Oncotarget. 2016; 7(41): 1-15.
[11] Mirzaei H, Masoudifar A, Sahebkar A, Zare N, Sadri Nahand J, Rashidi B, Mehrabian E, Mohammadi M, Mirzaei HR, Jaafari MR. MicroRNA: a novel target of curcumin in cancer therapy. J Cell Physiol. 2018; 233(4): 3004-3015.
[12] Mirzaei H, Naseri G, Rezaee R, Mohammadi M, Banikazemi Z, Mirzaei HR, Salehi H, Peyvandi M, Pawelek JM, Sahebkar A. Curcumin: a new candidate for melanoma therapy? Int J Cancer. 2016; 139(8): 1683-1695.
[13] Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A, Stang A, Roasch A, Ugurel S. Melanoma. Lancet. 2018; 392(10151): 971-984.
[14] Dahmke IN, Backes C, Rudzitis-Auth J, Laschke MW, Leidinger P, Menger MD, Meese E, Mahlknecht U. Curcumin intake affects miRNA signature in murine melanoma with mmu-miR-205-5p most significantly altered. PLoS One. 2013; 8(12): 1-10.
[15] Smoot ME, Ono K, Ruscheinski J, Wang P-L, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011; 27(3): 431-442.
[16] Bindea G, Galon J, Mlecnik B. CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data. Bioinformatics. 2013; 29(5): 661-663.
[17] Babicki S, Arndt D, Marcu A, Liang Y, Grant JR, Maciejewski A, Wishart DS. Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res. 2016; 44: 147-153.
[18] Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8): 1091-1093.
[19] Norouzinia M, Azodi MZ, Seyfi DN, Kardan A, Naseh A, Akbari Z. Predication of hub target genes of differentially expressed microRNAs contributing in Helicobacter Pylori infection in gastric non-cancerous tissue. Gastroenterol Hepatol Bed Bench. 2019; 12(S1): 44-50.
[20] Zhou J, Liu R, Wang Y, Tang J, Tang S, Chen X, Xia K, Xiong W, Xu D, Wang S, He Q, Cao K. Mir-199a-5p regulates the expression of metastasis-associated genes in B16F10 melanoma cells. Int J Clin Exp Path.  2014; 7(10): 7182-7190.
[21] Murakami Y, Toyoda H, Tanaka M, Kuroda M, Harada Y, Matsuda F, Tajima A, Kosaka N, Ochyia T, Shimotohni K. The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families. PLoS One. 2011; 6(1): e16081.
[22] El Azzouzi H, Leptidis S, Dirkx E, Hoeks J, van Bree B, Brand K, McClellan EA, Poels E, Sluimer JC, van den Hoogenhof MM, Armand AS, Yin X, Langley S, Bourajjaj M, Olieslagers S, Krishnan J, Vooijs M, Kurihara H, Stubbs A, Pinto YM, Krek W, Mayr M, da Costa Martins PA, Schrauwen P, De Windt LJ. The hypoxia-inducible microRNA cluster miR-199a∼ 214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metab. 2013; 18(3): 341-354.
[23] Kim S, Lee UJ, Kim MN, Lee E-J, Kim JY, Lee MY, Choung S, Kim YJ, Choi YC. MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2). J Biological Chem. 2008; 283(26): 18158-18166.
[24] Philippidou D, Schmitt M, Moser D, Margue C, Nazarov PV, Muller A, Vallar L, Nashan D, Behrmann I, Kreis S. Signatures of microRNAs and selected microRNA target genes in human melanoma. Cancer Res. 2010; 70(10): 4163-4173.
[25] Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, Trujillo JP, Minguillón J, Ramírez MJ, Pujol R, Casado JA, Baños R, Rio P, Knies K, Zúñiga S, Benítez J, Bueren JA, Jaspers NG, Schärer OD, de Winter JP, Schindler D, Surrallés J. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013; 92(5): 800-806.
[26] Biggerstaff M, Szymkowski DE, Wood RD. Co‐correction of the ERCC1, ERCC4 and xeroderma pigmentosum group F DNA repair defects in vitro. EMBO J. 1993; 12(9): 3685-3692.
[27] Kornguth DG, Garden AS, Zheng Y, Dahlstrom KR, Wei Q, Sturgis EM. Gastrostomy in oropharyngeal cancer patients with ERCC4 (XPF) germline variants. Int J Radiat Oncol Biol Phys.2005; 62(3): 665-671.
[28] Milne RL, Ribas G, González-Neira A, Fagerholm R, Salas A, González E, Dopazo J, Nevanlinna H, Robledo M, Benitez J. ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping. Cancer Res. 2006; 66(19): 9420-9427.
[29] Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D. Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity. J Neurosci. 2012; 32(12): 4240-4246.
[30] Di Fonzo A, Chien H, Socal M, Giraudo S, Tassorelli C, Iliceto G, Fabbrini G, Marconi R, Fincati E, Abbruzzese G, Marini P, Squitieri F, Horstink MW, Montagna P, Libera AD, Stocchi F, Goldwurm S, Ferreira JJ, Meco G, Martignoni E, Lopiano L, Jardim LB, Oostra BA, Barbosa ER, Italian Parkinson Genetics Network, Bonifati V. ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology. 2007; 68(19): 1557-1562.
[31] Hart T, Gorry M, Hart P, Woodard A, Shihabi Z, Sandhu J,  Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet. 2002; 39(12): 882-892.
[32] Padmanabhan S, Melander O, Johnson T, Di Blasio AM, Lee WK, Gentilini D,  Hastie CE, Menni C, Monti MC, Delles C, Laing S, Corso B, Navis G, Kwakernaak AJ, van der Harst P, Bochud M, Maillard M, Burnier M, Hedner T, Kjeldsen S, Wahlstrand B, Sjögren M, Fava C, Montagnana M, Danese E, Torffvit O, Hedblad B, Snieder H, Connell JM, Brown M, Samani NJ, Farrall M, Cesana G, Mancia G, Signorini S, Grassi G, Eyheramendy S, Wichmann HE, Laan M, Strachan DP, Sever P, Shields DC, Stanton A, Vollenweider P, Teumer A, Völzke H, Rettig R, Newton-Cheh C, Arora P, Zhang F, Soranzo N, Spector TD, Lucas G, Kathiresan S, Siscovick DS, Luan J, Loos RJ, Wareham NJ, Penninx BW, Nolte IM, McBride M, Miller WH, Nicklin SA, Baker AH, Graham D, McDonald RA, Pell JP, Sattar N, Welsh P; Global BPgen Consortium, Munroe P, Caulfield MJ, Zanchetti A, Dominiczak AF. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet. 2010; 6(10): 1-11.
[33] Demirag GG, Sullu Y, Yucel I. Expression of Plakophilins (PKP1, PKP2, and PKP3) in breast cancers. Med Oncol. 2012; 29(3): 1518-1522.
[34] Demirag GG, Sullu Y, Gurgenyatagi D, Okumus NO, Yucel I. Expression of plakophilins (PKP1, PKP2, and PKP3) in gastric cancers. Diagn Pathol. 2011; 6(1): 1-5.