Melatonin suppresses epithelial‑to‑mesenchymal transition in the MG‑63 cell line

Chen,Yongjun; Zhang,Tao; Liu,Xiongwei; Li,Zengyan; Zhou,Dongming; Xu,Wensheng

doi:10.3892/mmr.2019.10902

Melatonin suppresses epithelial‑to‑mesenchymal transition in the MG‑63 cell line

Authors:
- Yongjun Chen
- Tao Zhang
- Xiongwei Liu
- Zengyan Li
- Dongming Zhou
- Wensheng Xu
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Affiliations: Department of Orthopaedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, P.R. China, Department of Immunology, Basic and Forensic Medicine of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014060, P.R. China, Department of Nephrology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014010, P.R. China
Published online on: December 23, 2019 https://doi.org/10.3892/mmr.2019.10902
Pages: 1356-1364

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Abstract

Epithelial‑to‑mesenchymal transition (EMT) is a major process involved in tumor progression and metastasis. Melatonin is secreted by the pineal gland and has been documented as a potential therapeutic agent for multiple tumors. However, the effects of melatonin on EMT during osteosarcoma (OA) development remain undefined. The present study explored the biological functions and effects of melatonin on EMT induced by transforming growth factor β1 (TGF‑β1) and its underlying mechanisms in MG‑63 cells. Using western‑blotting and immunofluorescence, it was found that the switch in E‑cadherin/N‑cadherin and vimentin expression was induced by TGF‑β1, which was reversed by melatonin through the suppression of Snail and matrix metalloproteinase 9 (MMP‑9), through hypoxia‑inducible factor 1α (HIF‑1α) inhibition. These findings demonstrated that the anticancer effects of melatonin against OA MG‑63 cells is through the suppression of EMT via HIF‑1α/Snail/MMP‑9 signaling.

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1	Basu-Roy U, Basilico C and Mansukhani A: Perspectives on cancer stem cells in osteosarcoma. Cancer Lett. 338:158–167. 2013. View Article : Google Scholar : PubMed/NCBI
2	Marina N, Gebhardt M, Teot L and Gorlick R: Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 9:422–441. 2004. View Article : Google Scholar : PubMed/NCBI
3	Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM and Pandi-Perumal SR: Melatonin-a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 93:350–384. 2011. View Article : Google Scholar : PubMed/NCBI
4	Fernández Vázquez G, Reiter RJ and Agil A: Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: Implications for obesity control. J Pineal Res. 64:e124722018. View Article : Google Scholar : PubMed/NCBI
5	Karamitri A and Jockers R: Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol. 15:105–125. 2019. View Article : Google Scholar : PubMed/NCBI
6	Haeger P, Bouchet A, Ossandon C and Bresky G: Treatment with melatonin improves cognitive behavior and motor skills in a rat model of liver fibrosis. Ann Hepatol. 18:101–108. 2019. View Article : Google Scholar : PubMed/NCBI
7	Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP and Li HB: Melatonin for the prevention and treatment of cancer. Oncotarget. 8:39896–39921. 2017.PubMed/NCBI
8	Parkin DM: International variation. Oncogene. 23:6329–6340. 2004. View Article : Google Scholar : PubMed/NCBI
9	Jablonska K, Pula B, Zemla A, Kobierzycki C, Kedzia W, Nowak-Markwitz E, Spaczynski M, Zabel M, Podhorska-Okolow M and Dziegiel P: Expression of the MT1 melatonin receptor in ovarian cancer cells. Int J Mol Sci. 15:23074–23089. 2014. View Article : Google Scholar : PubMed/NCBI
10	Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF and Xu K: Melatonin, a full service anti-cancer agent: Inhibition of initiation, progression and metastasis. Int J Mol Sci. 18(pii): E8432017. View Article : Google Scholar : PubMed/NCBI
11	Menéndez-Menéndez J, Hermida-Prado F, Granda-Díaz R, González A, García-Pedrero JM, Del-Río-Ibisate N, González-González A, Cos S, Alonso-González C and Martínez-Campa C: Deciphering the molecular basis of melatonin protective effects on breast cells treated with doxorubicin: TWIST1 a transcription factor involved in EMT and metastasis, a novel target of melatonin. Cancers (Basel). 11(pii): E10112019. View Article : Google Scholar : PubMed/NCBI
12	Mao L, Dauchy RT, Blask DE, Slakey LM, Xiang S, Yuan L, Dauchy EM, Shan B, Brainard GC, Hanifin JP, et al: Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β. Mol Endocrinol. 26:1808–1820. 2012. View Article : Google Scholar : PubMed/NCBI
13	Seba V, Silva G, Santos MBD, Baek SJ, França SC, Fachin AL, Regasini LO and Marins M: Chalcone derivatives 4′-amino-1-naphthyl-chalcone (D14) and 4′-amino-4-methyl-1-naphthyl-chalcone (D15) suppress migration and invasion of osteosarcoma cells mediated by p53 regulating EMT-related genes. Int J Mol Sci. 19(pii): E28382018. View Article : Google Scholar : PubMed/NCBI
14	Suzuki S, Toyoma S, Tsuji T, Kawasaki Y and Yamada T: CD147 mediates transforming growth factor-β1-induced epithelial-mesenchymal transition and cell invasion in squamous cell carcinoma of the tongue. Exp Ther Med. 17:2855–2860. 2019.PubMed/NCBI
15	Li L, Qi L, Liang Z, Song W, Liu Y, Wang Y, Sun B, Zhang B and Cao W: Transforming growth factor-β1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells. Int J Mol Med. 36:113–122. 2015. View Article : Google Scholar : PubMed/NCBI
16	Gonçalves Ndo N, Colombo J, Lopes JR, Gelaleti GB, Moschetta MG, Sonehara NM, Hellmén E, Zanon Cde F, Oliani SM and Zuccari DA: Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines. PLoS One. 11:e01504072016. View Article : Google Scholar : PubMed/NCBI
17	Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, Bhattacharya S and Basu A: Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep. 6:219032016. View Article : Google Scholar : PubMed/NCBI
18	Ha JH, Ward JD, Radhakrishnan R, Jayaraman M, Song YS and Dhanasekaran DN: Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus. Oncotarget. 7:37664–37679. 2016. View Article : Google Scholar : PubMed/NCBI
19	Park JH and Yoon J: Schizandrin inhibits fibrosis and epithelial-mesenchymal transition in transforming growth factor-β1-stimulated AML12 cells. Int Immunopharmacol. 25:276–284. 2015. View Article : Google Scholar : PubMed/NCBI
20	Amaar YG and Reeves ME: RASSF1C regulates miR-33a and EMT marker gene expression in lung cancer cells. Oncotarget. 10:123–132. 2019. View Article : Google Scholar : PubMed/NCBI
21	Rubina KA, Surkova EI, Semina EV, Sysoeva VY, Kalinina NI, Poliakov AA, Treshalina HM and Tkachuk VA: T-Cadherin expression in melanoma cells stimulates stromal cell recruitment and invasion by regulating the expression of chemokines, integrins and adhesion molecules. Cancers (Basel). 7:1349–1370. 2015. View Article : Google Scholar : PubMed/NCBI
22	Huang H, Nie C, Qin X, Zhou J and Zhang L: Diosgenin inhibits the epithelial-mesenchymal transition initiation in osteosarcoma cells via the p38MAPK signaling pathway. Oncol Lett. 18:4278–4287. 2019.PubMed/NCBI
23	Fan S, Gao X, Chen P and Li X: Carboxypeptidase E-ΔN promotes migration, invasiveness, and epithelial-mesenchymal transition of human osteosarcoma cells via the Wnt-β-catenin pathway. Biochem Cell Biol. 97:446–453. 2019. View Article : Google Scholar : PubMed/NCBI
24	Zhao H, Peng C, Lu X, Guo M, Yang T, Zhou J and Hai Y: PDCD5 inhibits osteosarcoma cell metastasis via targeting TGF-β1/Smad signaling pathway and is associated with good prognosis. Am J Transl Res. 11:1116–1128. 2019.PubMed/NCBI
25	Sung JY, Park SY, Kim JH, Kang HG, Yoon JH, Na YS, Kim YN and Park BK: Interferon consensus sequence-binding protein (ICSBP) promotes epithelial-to-mesenchymal transition (EMT)-like phenomena, cell-motility, and invasion via TGF-β signaling in U2OS cells. Cell Death Dis. 5:e12242014. View Article : Google Scholar : PubMed/NCBI
26	Baba K, Davidson AJ and Tosini G: Melatonin entrains PER2:LUC bioluminescence circadian rhythm in the mouse cornea. Invest Ophthalmol Vis Sci. 56:4753–4758. 2015. View Article : Google Scholar : PubMed/NCBI
27	Dijk DJ, Duffy JF, Riel E, Shanahan TL and Czeisler CA: Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol. 516:611–627. 1999. View Article : Google Scholar : PubMed/NCBI
28	Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P and Govitrapong P: Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci. 15:16848–16884. 2014. View Article : Google Scholar : PubMed/NCBI
29	Mao L, Summers W, Xiang S, Yuan L, Dauchy RT, Reynolds A, Wren-Dail MA, Pointer D, Frasch T, Blask DE and Hill SM: Melatonin represses metastasis in Her2-postive human breast cancer cells by suppressing RSK2 expression. Mol Cancer Res. 14:1159–1169. 2016. View Article : Google Scholar : PubMed/NCBI
30	Tai SY, Huang SP, Bao BY and Wu MT: Urinary melatonin-sulfate/cortisol ratio and the presence of prostate cancer: A case-control study. Sci Rep. 6:296062016. View Article : Google Scholar : PubMed/NCBI
31	Sonehara NM, Lacerda JZ, Jardim-Perassi BV, de Paula Jr R Jr, Moschetta-Pinheiro MG, Souza YST, de Andrade JCJ and De Campos Zuccari DAP: Melatonin regulates tumor aggressiveness under acidosis condition in breast cancer cell lines. Oncol Lett. 17:1635–1645. 2019.PubMed/NCBI
32	Zou ZW, Liu T, Li Y, Chen P, Peng X, Ma C, Zhang WJ and Li PD: Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS. Redox Biol. 16:226–236. 2018. View Article : Google Scholar : PubMed/NCBI
33	Fic M, Gomulkiewicz A, Grzegrzolka J, Podhorska-Okolow M, Zabel M, Dziegiel P and Jablonska K: The impact of melatonin on colon cancer cells' resistance to doxorubicin in an in vitro study. Int J Mol Sci. 18(pii): E13962017. View Article : Google Scholar : PubMed/NCBI
34	Kaufhold S and Bonavida B: Central role of Snail1 in the regulation of EMT and resistance in cancer: A target for therapeutic intervention. J Exp Clin Cancer Res. 33:622014. View Article : Google Scholar : PubMed/NCBI
35	Guo L, Sun C, Xu S, Xu Y, Dong Q, Zhang L, Li W, Wang X, Ying G and Guo F: Knockdown of long non-coding RNA linc-ITGB1 inhibits cancer stemness and epithelial-mesenchymal transition by reducing the expression of Snail in non-small cell lung cancer. Thorac Cancer. 10:128–136. 2019. View Article : Google Scholar : PubMed/NCBI
36	Naber HP, Drabsch Y, Snaar-Jagalska BE, ten Dijke P and van Laar T: Snail and Slug, key regulators of TGF-β-induced EMT, are sufficient for the induction of single-cell invasion. Biochem Biophys Res Commun. 435:58–63. 2013. View Article : Google Scholar : PubMed/NCBI
37	Cheng J, Yang HL, Gu CJ, Liu YK, Shao J, Zhu R, He YY, Zhu XY and Li MQ: Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF. Int J Mol Med. 43:945–955. 2019.PubMed/NCBI
38	Singh SK, Mishra MK and Singh R: Hypoxia-inducible factor-1α induces CX3CR1 expression and promotes the epithelial to mesenchymal transition (EMT) in ovarian cancer cells. J Ovarian Res. 12:422019. View Article : Google Scholar : PubMed/NCBI