Abstract
(−)-Epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea, has been demonstrated to have anticancer effects in a wide variety of human cancer. MicroRNAs (miRNAs) are a class of short noncoding RNAs and play important role in gene regulation and are critically involved in the pathogenesis and progression of human cancer. This study aims to investigate the effects of EGCG on osteosarcoma (OS) cells and elucidate the underlying mechanism. Cellular function assays revealed that EGCG inhibited cell proliferation, induced cell cycle arrest and promoted apoptosis of OS cells in vitro, and also inhibited the growth of transplanted tumors in vivo. By miRNA microarray and RT-qPCR analysis, miR-1 was found to be significantly upregulated in MG-63 and U-2OS treated by EGCG in dose- and time-dependent manners, and miR-1 downregulation by inhibitor mimics attenuated EGCG-induced inhibition on cell growth of OS cells. We also confirmed that miR-1 was also frequently decreased in clinical OS tumor tissues. Moreover, both EGCG and miR-1 mimic inhibited c-MET expression, and combination treatment with EGCG and c-MET inhibitor (crizotinib) had enhanced inhibitory effects on the growth of MG-63 and U-2OS cells. Taken together, these results suggest that EGCG has an anticancer effect on OS cells, at least partially, through regulating miR-1/c-MET interaction.
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References
Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev. 2014;40:523–32.
He H, Ni J, Huang J. Molecular mechanisms of chemoresistance in osteosarcoma (review). Oncol Lett. 2014;7:1352–62.
Chen D, Wan SB, Yang H, Yuan J, Chan TH, Dou QP. Egcg, green tea polyphenols and their synthetic analogs and prodrugs for human cancer prevention and treatment. Adv Clin Chem. 2011;53:155–77.
Lamoral-Theys D, Pottier L, Dufrasne F, Neve J, Dubois J, Kornienko A, et al. Natural polyphenols that display anticancer properties through inhibition of kinase activity. Curr Med Chem. 2010;17:812–25.
Garg AK, Buchholz TA, Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal. 2005;7:1630–47.
Fujiki H, Suganuma M, Kurusu M, Okabe S, Imayoshi Y, Taniguchi S, et al. New tnf-alpha releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with egcg and sulindac or tamoxifen. Mutat Res. 2003;523–524:119–25.
Suganuma M, Saha A, Fujiki H. New cancer treatment strategy using combination of green tea catechins and anticancer drugs. Cancer Sci. 2011;102:317–23.
Bartel DP. Micrornas: target recognition and regulatory functions. Cell. 2009;136:215–33.
Farazi TA, Spitzer JI, Morozov P, Tuschl T. Mirnas in human cancer. J Pathol. 2011;223:102–15.
Milenkovic D, Jude B, Morand C. Mirna as molecular target of polyphenols underlying their biological effects. Free Radic Biol Med. 2013;64:40–51.
Sethi S, Li Y, Sarkar FH. Regulating mirna by natural agents as a new strategy for cancer treatment. Curr Drug Targets. 2013;14:1167–74.
Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, et al. Targeting mirnas involved in cancer stem cell and emt regulation: an emerging concept in overcoming drug resistance. Drug Resist Updat Rev Commentaries Antimicrob Anticancer Chemother. 2010;13:109–18.
Zhang J, Chen YL, Ji G, Fang W, Gao Z, Liu Y, et al. Sorafenib inhibits epithelial-mesenchymal transition through an epigenetic-based mechanism in human lung epithelial cells. PLoS One. 2013;8, e64954.
Schramm L. Going green: the role of the green tea component egcg in chemoprevention. J Carcinogenesis Mutagen. 2013;4:1000142.
Park JS, Khoi PN, Joo YE, Lee YH, Lang SA, Stoeltzing O, et al. Egcg inhibits recepteur d’origine nantais expression by suppressing egr-1 in gastric cancer cells. Int J Oncol. 2013;42:1120–6.
Ogawa K, Hara T, Shimizu M, Nagano J, Ohno T, Hoshi M, et al. (−)-epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells. Oncol Lett. 2012;4:546–50.
Ma YC, Li C, Gao F, Xu Y, Jiang ZB, Liu JX, et al. Epigallocatechin gallate inhibits the growth of human lung cancer by directly targeting the egfr signaling pathway. Oncol Rep. 2014;31:1343–9.
Braicu C, Gherman CD, Irimie A, Berindan-Neagoe I. Epigallocatechin-3-gallate (egcg) inhibits cell proliferation and migratory behaviour of triple negative breast cancer cells. J Nanosci Nanotechnol. 2013;13:632–7.
Trudel D, Labbe DP, Araya-Farias M, Doyen A, Bazinet L, Duchesne T, et al. A two-stage, single-arm, phase ii study of egcg-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer. Gynecol Oncol. 2013;131:357–61.
Hsieh TC, Wu JM. Targeting cwr22rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals egcg, genistein and quercetin. Anticancer Res. 2009;29:4025–32.
Hwang JT, Ha J, Park IJ, Lee SK, Baik HW, Kim YM, et al. Apoptotic effect of egcg in ht-29 colon cancer cells via ampk signal pathway. Cancer Lett. 2007;247:115–21.
Park IJ, Lee YK, Hwang JT, Kwon DY, Ha J, Park OJ. Green tea catechin controls apoptosis in colon cancer cells by attenuation of h2o2-stimulated cox-2 expression via the ampk signaling pathway at low-dose h2o2. Ann N Y Acad Sci. 2009;1171:538–44.
Xu L, Zhang Y, Wang H, Zhang G, Ding Y, Zhao L. Tumor suppressor mir-1 restrains epithelial-mesenchymal transition and metastasis of colorectal carcinoma via the mapk and pi3k/akt pathway. J Transl Med. 2014;12:244.
Kawakami K, Enokida H, Chiyomaru T, Tatarano S, Yoshino H, Kagara I, et al. The functional significance of mir-1 and mir-133a in renal cell carcinoma. Eur J Cancer. 2012;48:827–36.
Li D, Yang P, Li H, Cheng P, Zhang L, Wei D, et al. Microrna-1 inhibits proliferation of hepatocarcinoma cells by targeting endothelin-1. Life Sci. 2012;91:440–7.
Yoshino H, Chiyomaru T, Enokida H, Kawakami K, Tatarano S, Nishiyama K, et al. The tumour-suppressive function of mir-1 and mir-133a targeting tagln2 in bladder cancer. Br J Cancer. 2011;104:808–18.
Hudson RS, Yi M, Esposito D, Watkins SK, Hurwitz AA, Yfantis HG, et al. Microrna-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer. Nucleic Acids Res. 2012;40:3689–703.
Novello C, Pazzaglia L, Cingolani C, Conti A, Quattrini I, Manara MC, et al. Mirna expression profile in human osteosarcoma: role of mir-1 and mir-133b in proliferation and cell cycle control. Int J Oncol. 2013;42:667–75.
Sampson ER, Martin BA, Morris AE, Xie C, Schwarz EM, O’Keefe RJ, et al. The orally bioavailable met inhibitor pf-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model. J Bone Miner Res Off J Am Soc Bone Miner Res. 2011;26:1283–94.
Migliore C, Martin V, Leoni VP, Restivo A, Atzori L, Petrelli A, et al. Mir-1 downregulation cooperates with macc1 in promoting met overexpression in human colon cancer. Clinical Cancer Res Off J Am Assoc Cancer Res. 2012;18:737–47.
Nasser MW, Datta J, Nuovo G, Kutay H, Motiwala T, Majumder S, et al. Down-regulation of micro-rna-1 (mir-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by mir-1. J Biol Chem. 2008;283:33394–405.
Yan D, Dong Xda E, Chen X, Wang L, Lu C, Wang J, et al. Microrna-1/206 targets c-met and inhibits rhabdomyosarcoma development. J Biol Chem. 2009;284:29596–604.
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Zhu, K., Wang, W. Green tea polyphenol EGCG suppresses osteosarcoma cell growth through upregulating miR-1. Tumor Biol. 37, 4373–4382 (2016). https://doi.org/10.1007/s13277-015-4187-3
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DOI: https://doi.org/10.1007/s13277-015-4187-3