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Current Cancer Drug Targets

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ISSN (Online): 1873-5576

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Research Article

MALAT1 Promotes Tumorigenesis and Increases Cellular Sensitivity to Herceptin in HER2-positive Breast Cancer

Author(s): Chuansheng Yang, Hongbo Zhu, Yeru Tan, Renjie Zhu, Xiaoping Wu, Yuehua Li* and Cunchuan Wang*

Volume 21, Issue 10, 2021

Published on: 18 June, 2021

Page: [860 - 869] Pages: 10

DOI: 10.2174/1568009621666210618164300

Price: $65

Abstract

Background: The function of MALAT1, a long non-coding RNAs (lncRNA), in HER2- positive breast cancer remains largely unexplored.

Objectives: This study aimed to investigate the effect of MALAT1 on tumor development in HER2-positive breast cancer.

Methods: We detected MALAT1 expression in HER2-positive breast cancer cells and tissues, and analyzed the effects of MALAT1 on cell proliferation in HER2-positive breast cancer cells lines (BT-474 and SKBR3). A mouse xenograft model was established for detecting the function of MALAT1 in HER2-positive breast cancer.

Results and Discussion: As a result, MALAT1 was remarkably up-regulated in HER2-positive breast cancer both in cells and tissues. In addition, the silencing of MALAT1 inhibited the proliferation of HER2-positive breast cancer cells both in vitro and in vivo. Furthermore, knockdown of MALAT1 by shRNA down-regulated DNMT1, DNMT3a, and DNMT3b, while up-regulated BRCA1 and PTEN in HER2-positive breast cancer both in cell lines and mouse xenograft models.

Conclusion: In short, MALAT1 might be a potential biomarker and therapeutic target for HER2- positive breast cancer therapy.

Keywords: HER2-positive breast cancer, long non-coding RNA, MALAT1, DNMTs, tumorigenesis, herceptin resistance.

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[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Prat, A.; Pineda, E.; Adamo, B.; Galván, P.; Fernández, A.; Gaba, L.; Díez, M.; Viladot, M.; Arance, A.; Muñoz, M. Clinical implications of the intrinsic molecular subtypes of breast cancer. 2015, 24, S26-S35.
[http://dx.doi.org/10.1016/j.breast.2015.07.008]
[3]
DeSantis, C.E.; Ma, J.; Gaudet, M.M.; Newman, L.A.; Miller, K.D.; Goding Sauer, A.; Jemal, A.; Siegel, R.L. Breast cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(6), 438-451.
[http://dx.doi.org/10.3322/caac.21583] [PMID: 31577379]
[4]
Krop, I.E.; Kim, S-B.; Martin, A.G.; LoRusso, P.M.; Ferrero, J.M.; Badovinac-Crnjevic, T.; Hoersch, S.; Smitt, M.; Wildiers, H. Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): Final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol., 2017, 18(6), 743-754.
[http://dx.doi.org/10.1016/S1470-2045(17)30313-3] [PMID: 28526538]
[5]
Tóth, G.; Szöőr, A.; Simon, L.; Yarden, Y.; Szöllősi, J.; Vereb, G. The combination of trastuzumab and pertuzumab administered at approved doses may delay development of trastuzumab resistance by additively enhancing antibody-dependent cell-mediated cytotoxicity. 2016, 8(7), 1361-1370.
[http://dx.doi.org/10.1080/19420862.2016.1204503]
[6]
Dawood, S.; Broglio, K.; Buzdar, A.U.; Hortobagyi, G.N.; Giordano, S.H. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: An institutional-based review. J. Clin. Oncol., 2010, 28(1), 92-98.
[http://dx.doi.org/10.1200/JCO.2008.19.9844] [PMID: 19933921]
[7]
Mohd Sharial, M.S.N.; Crown, J.; Hennessy, B.T. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Ann. Oncol., 2012, 23(12), 3007-3016.
[http://dx.doi.org/10.1093/annonc/mds200] [PMID: 22865781]
[8]
Zhang, Y.; Tang, L. The application of lncrnas in cancer treatment and diagnosis. Recent Pat. Anticancer Drug Discov., 2018, 13(3), 292-301.
[9]
Lorenzen, J.M.; Thum, T. Long noncoding RNAs in kidney and cardiovascular diseases. Nat. Rev. Nephrol., 2016, 12(6), 360-373.
[http://dx.doi.org/10.1038/nrneph.2016.51]
[10]
Liu, H.; Luo, J.; Luan, S.; He, C.; Li, Z. Long non-coding RNAs involved in cancer metabolic reprogramming. Cell. Mol. Life Sci., 2019, 76(3), 495-504.
[http://dx.doi.org/10.1007/s00018-018-2946-1] [PMID: 30341461]
[11]
Schmitt, A.M.; Chang, H.Y. Long noncoding rnas in cancer pathways. Cancer Cell., 2016, 29(4), 452-463.
[http://dx.doi.org/10.1016/j.ccell.2016.03.010]
[12]
Jen, J.; Tang, Y.A.; Lu, Y.H.; Lin, C.C.; Lai, W.W.; Wang, Y.C. Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression. Mol. Cancer, 2017, 16(1), 104.
[http://dx.doi.org/10.1186/s12943-017-0674-z] [PMID: 28615056]
[13]
Chakravarty, D.; Sboner, A.; Nair, S.S.; Giannopoulou, E.; Li, R.; Hennig, S.; Mosquera, J.M.; Pauwels, J.; Park, K.; Kossai, M.; MacDonald, T.Y.; Fontugne, J.; Erho, N.; Vergara, I.A.; Ghadessi, M.; Davicioni, E.; Jenkins, R.B.; Palanisamy, N.; Chen, Z.; Nakagawa, S.; Hirose, T.; Bander, N.H.; Beltran, H.; Fox, A.H.; Elemento, O.; Rubin, M.A. The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat. Commun., 2014, 5, 5383.
[http://dx.doi.org/10.1038/ncomms6383] [PMID: 25415230]
[14]
YiRen, H.; YingCong, Y.; Sunwu, Y.; Keqin, L.; Xiaochun, T.; Senrui, C.; Ende, C.; XiZhou, L.; Yanfan, C. Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer. Mol. Cancer, 2017, 16(1), 174.
[http://dx.doi.org/10.1186/s12943-017-0743-3] [PMID: 29162158]
[15]
Lin, N.; Yao, Z.; Xu, M.; Chen, J.; Lu, Y.; Yuan, L.; Zhou, S.; Zou, X.; Xu, R. Long noncoding RNA MALAT1 potentiates growth and inhibits senescence by antagonizing ABI3BP in gallbladder cancer cells. J. Exp. Clin. Cancer Res., 2019, 38(1), 244.
[http://dx.doi.org/10.1186/s13046-019-1237-5] [PMID: 31174563]
[16]
Wu, S.S.; Sun, H.; Wang, Y.J.; Yang, X.; Meng, Q.T.; Yang, H.B.; Zhu, H.T.; Tang, W.Y.; Li, X.B.; Aschner, M.; Chen, R. 2019.
[17]
Schmidt, L.H.; Spieker, T.; Koschmieder, S.; Schäffers, S.; Humberg, J.; Jungen, D.; Bulk, E.; Hascher, A.; Wittmer, D.; Marra, A.; Hillejan, L.; Wiebe, K.; Berdel, W.E.; Wiewrodt, R.; Muller-Tidow, C. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J. Thorac. Oncol., 2011, 6(12), 1984-1992.
[http://dx.doi.org/10.1097/JTO.0b013e3182307eac]
[18]
Guffanti, A.; Iacono, M.; Pelucchi, P.; Kim, N.; Soldà, G.; Croft, L.J.; Taft, R.J.; Rizzi, E.; Askarian-Amiri, M.; Bonnal, R.J.; Callari, M.; Mignone, F.; Pesole, G.; Bertalot, G.; Bernardi, L.R.; Albertini, A.; Lee, C.; Mattick, J.S.; Zucchi, I.; De Bellis, G. A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. BMC Genomics, 2009, 10, 163.
[http://dx.doi.org/10.1186/1471-2164-10-163] [PMID: 19379481]
[19]
Li, X.; Chen, N.; Zhou, L.; Wang, C.; Wen, X.; Jia, L.; Cui, J.; Hoffman, A.R.; Hu, J.F.; Li, W. Genome-wide target interactome profiling reveals a novel EEF1A1 epigenetic pathway for oncogenic lncRNA MALAT1 in breast cancer. Am. J. Cancer Res., 2019, 9(4), 714-729.
[PMID: 31105998]
[20]
Shi, D.M.; Li, L.X.; Bian, X.Y.; Shi, X.J.; Lu, L.L.; Zhou, H.X.; Pan, T.J.; Zhou, J.; Fan, J.; Wu, W.Z. miR-296-5p suppresses EMT of hepatocellular carcinoma via attenuating NRG1/ERBB2/ERBB3 signaling. J. Exp. Clin. Cancer Res., 2018, 37(1), 294.
[http://dx.doi.org/10.1186/s13046-018-0957-2] [PMID: 30486894]
[21]
Li, Y.; Zhang, Z.; Chen, J.; Liu, W.; Lai, W.; Liu, B.; Li, X.; Liu, L.; Xu, S.; Dong, Q.; Wang, M.; Duan, X.; Tan, J.; Zheng, Y.; Zhang, P.; Fan, G.; Wong, J.; Xu, G.L.; Wang, Z.; Wang, H.; Gao, S.; Zhu, B. Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature, 2018, 564(7734), 136-140.
[http://dx.doi.org/10.1038/s41586-018-0751-5] [PMID: 30487604]
[22]
Yu, Z.; Xiao, Q.; Zhao, L.; Ren, J.; Bai, X.; Sun, M.; Wu, H.; Liu, X.; Song, Z.; Yan, Y.; Mi, X.; Wang, E.; Jin, F.; Wei, M. DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis. Mol. Carcinog., 2015, 54(9), 707-719.
[http://dx.doi.org/10.1002/mc.22133] [PMID: 24464625]
[23]
Lee, C.F.; Ou, D.S.C.; Lee, S.B.; Chang, L.H.; Lin, R.K.; Li, Y.S.; Upadhyay, A.K.; Cheng, X.; Wang, Y.C.; Hsu, H.S.; Hsiao, M.; Wu, C.W.; Juan, L.J. hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing. J. Clin. Invest., 2010, 120(8), 2920-2930.
[http://dx.doi.org/10.1172/JCI42275] [PMID: 20592467]
[24]
Bárcena-Varela, M.; Caruso, S.; Llerena, S.; Álvarez-Sola, G.; Uriarte, I.; Latasa, M.U.; Urtasun, R.; Rebouissou, S.; Alvarez, L.; Jimenez, M.; Santamaría, E.; Rodriguez-Ortigosa, C.; Mazza, G.; Rombouts, K.; San José-Eneriz, E.; Rabal, O.; Agirre, X.; Iraburu, M.; Santos-Laso, A.; Banales, J.M.; Zucman-Rossi, J.; Prósper, F.; Oyarzabal, J.; Berasain, C.; Ávila, M.A.; Fernández-Barrena, M.G. Dual targeting of histone methyltransferase g9a and dna-methyltransferase 1 for the treatment of experimental hepatocellular carcinoma. Hepatology, 2019, 69(2), 587-603.
[http://dx.doi.org/10.1002/hep.30168] [PMID: 30014490]
[25]
Muvarak, N.E.; Chowdhury, K.; Xia, L.; Robert, C.; Choi, E.Y.; Cai, Y.; Bellani, M.; Zou, Y.; Singh, Z.N.; Duong, V.H.; Rutherford, T.; Nagaria, P.; Bentzen, S.M.; Seidman, M.M.; Baer, M.R.; Lapidus, R.G.; Baylin, S.B.; Rassool, F.V. Enhancing the cytotoxic effects of parp inhibitors with dna demethylating agents - a potential therapy for cancer. Cancer Cell, 2016, 30(4), 637-650.
[http://dx.doi.org/10.1016/j.ccell.2016.09.002] [PMID: 27728808]
[26]
Pathania, R.; Ramachandran, S.; Elangovan, S.; Padia, R.; Yang, P.; Cinghu, S.; Veeranan-Karmegam, R.; Arjunan, P.; Gnana-Prakasam, J.P.; Sadanand, F.; Pei, L.; Chang, C.S.; Choi, J.H.; Shi, H.; Manicassamy, S.; Prasad, P.D.; Sharma, S.; Ganapathy, V.; Jothi, R.; Thangaraju, M. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat. Commun., 2015, 6, 6910.
[http://dx.doi.org/10.1038/ncomms7910] [PMID: 25908435]
[27]
Gijsen, M.; King, P.; Perera, T.; Parker, P.J.; Harris, A.L.; Larijani, B.; Kong, A. HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer. PLoS Biol., 2010, 8(12), e1000563.
[http://dx.doi.org/10.1371/journal.pbio.1000563] [PMID: 21203579]
[28]
Yue, D.; Qin, X. miR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells. Cancer Gene Ther., 2019, 26(1-2), 1-10.
[http://dx.doi.org/10.1038/s41417-018-0031-4] [PMID: 29925897]
[29]
Pickard, M.R.; Williams, G.T. Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: Implications for chemotherapy. Breast Cancer Res. Treat., 2014, 145(2), 359-370.
[http://dx.doi.org/10.1007/s10549-014-2974-y] [PMID: 24789445]
[30]
Sun, H.; Wang, G.; Peng, Y.; Zeng, Y.; Zhu, Q.N.; Li, T.L.; Cai, J.Q.; Zhou, H.H.; Zhu, Y.S. H19 lncRNA mediates 17β-estradiol-induced cell proliferation in MCF-7 breast cancer cells. Oncol. Rep., 2015, 33(6), 3045-3052.
[http://dx.doi.org/10.3892/or.2015.3899] [PMID: 25846769]
[31]
Hayes, E.L.; Lewis-Wambi, J.S. Mechanisms of endocrine resistance in breast cancer: An overview of the proposed roles of noncoding RNA. Breast Cancer Res., 2015, 17, 40.
[http://dx.doi.org/10.1186/s13058-015-0542-y] [PMID: 25849966]
[32]
Denis, H.; Ndlovu, M.N.; Fuks, F. Regulation of mammalian DNA methyltransferases: A route to new mechanisms. EMBO Rep., 2011, 12(7), 647-656.
[http://dx.doi.org/10.1038/embor.2011.110] [PMID: 21660058]
[33]
Dou, S.; Yao, Y.D.; Yang, X.Z.; Sun, T.M.; Mao, C.Q.; Song, E.W.; Wang, J. Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy. J. Control. Release, 2012, 161(3), 875-883.
[http://dx.doi.org/10.1016/j.jconrel.2012.05.015] [PMID: 22762887]
[34]
Zhou, W.; Jiang, Z.; Liu, N.; Xu, F.; Wen, P.; Liu, Y.; Zhong, W.; Song, X.; Chang, X.; Zhang, X.; Wei, G.; Yu, J. Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas. J. Cancer Res. Clin. Oncol., 2009, 135(1), 91-102.
[http://dx.doi.org/10.1007/s00432-008-0435-x] [PMID: 18670789]
[35]
Yong, H.; Wu, G.; Chen, J.; Liu, X.; Bai, Y.; Tang, N.; Liu, L.; Wei, J. LncRNA MALAT1 accelerates skeletal muscle cell apoptosis and inflammatory response in Sepsis by decreasing BRCA1 expression by recruiting EZH2. Mol. Ther. Nucleic Acids, 2020, 19, 97-108.
[http://dx.doi.org/10.1016/j.omtn.2019.10.028] [PMID: 31830649]
[36]
Burstein, H.J. The distinctive nature of HER2-positive breast cancers. N. Engl. J. Med., 2005, 353(16), 1652-1654.
[http://dx.doi.org/10.1056/NEJMp058197] [PMID: 16236735]
[37]
Nixon, N.A.; Hannouf, M.B.; Verma, S. A review of the value of human epidermal growth factor receptor 2 (HER2)-targeted therapies in breast cancer. Eur. J. Cancer, 2018, 89, 72-81.
[http://dx.doi.org/10.1016/j.ejca.2017.10.037] [PMID: 29241083]
[38]
Baselga, J.; Cortés, J.; Kim, S.B.; Im, S.A.; Hegg, R.; Im, Y.H.; Roman, L.; Pedrini, J.L.; Pienkowski, T.; Knott, A.; Clark, E.; Benyunes, M.C.; Ross, G.; Swain, S.M. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med., 2012, 366(2), 109-119.
[http://dx.doi.org/10.1056/NEJMoa1113216] [PMID: 22149875]
[39]
Valabrega, G.; Montemurro, F.; Aglietta, M. Trastuzumab: Mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann. Oncol., 2007, 18(6), 977-984.
[http://dx.doi.org/10.1093/annonc/mdl475] [PMID: 17229773]
[40]
Wang, D.S.; Liu, Z.X.; Lu, Y.X.; Bao, H.; Wu, X.; Zeng, Z.L.; Liu, Z.; Zhao, Q.; He, C.Y.; Lu, J.H.; Wang, Z.Q.; Qiu, M.Z.; Wang, F.; Wang, F.H.; Li, Y.H.; Wang, X.N.; Xie, D.; Jia, W.H.; Shao, Y.W.; Xu, R.H. Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer. Gut, 2019, 68(7), 1152-1161.
[http://dx.doi.org/10.1136/gutjnl-2018-316522] [PMID: 30269082]
[41]
Narayan, M.; Wilken, J.A.; Harris, L.N.; Baron, A.T.; Kimbler, K.D.; Maihle, N.J. Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res., 2009, 69(6), 2191-2194.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1056] [PMID: 19276389]
[42]
Dong, H.; Hu, J.; Zou, K.; Ye, M.; Chen, Y.; Wu, C.; Chen, X.; Han, M. Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer. Mol. Cancer, 2019, 18(1), 3.
[http://dx.doi.org/10.1186/s12943-018-0931-9] [PMID: 30621694]
[43]
Dong, H.; Wang, W.; Mo, S.; Liu, Q.; Chen, X.; Chen, R.; Zhang, Y.; Zou, K.; Ye, M.; He, X.; Zhang, F.; Han, J.; Hu, J. Long non- coding RNA SNHG14 induces trastuzumab resistance of breast cancer via regulating PABPC1 expression through H3K27 acetylation. J. Cell. Mol. Med., 2018, 22(10), 4935-4947.
[http://dx.doi.org/10.1111/jcmm.13758] [PMID: 30063126]
[44]
Wu, Y.; Sarkissyan, M.; Ogah, O.; Kim, J.; Vadgama, J.V. Expression of MALAT1 promotes trastuzumab resistance in HER2 overexpressing breast cancers. Cancers (Basel), 2020, 12(7), 1918.
[http://dx.doi.org/10.3390/cancers12071918] [PMID: 32708561]

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