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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

HOTAIR Competitively Binds MiRNA330 as a Molecular Sponge to Increase the Resistance of Gastric Cancer to Trastuzumab

Author(s): Liangyu Bie, Suxia Luo*, Dan Li, Yan Wei, Yu Mu, Xiaobing Chen, Saiqi Wang, Ping Guo and Xiaoyu Lu

Volume 20, Issue 9, 2020

Page: [700 - 709] Pages: 10

DOI: 10.2174/1568009620666200504114000

Price: $65


Background: HOTAIR, one of the most widely studied long non-coding RNAs in tumors, is closely related to tumor proliferation, migration, invasion and chemoresistance.

Objective: Here, we studied the mechanism behind proliferation and chemoresistance processes.

Methods: A total of 75 samples were collected from patients who underwent surgical resection of their gastric cancer and received trastuzumab treatment. Primary cells were isolated and cultured. We also developed a cell line overexpressing HOTAIR by constructing a lentiviral vector. These cell lines were studied using an array of established biomolecular methods.

Results: We found that HOTAIR levels were inversely associated with sensitivity to trastuzumab in gastric cancer and that overexpression of HOTAIR can promote the proliferation and invasion of gastric cancer cells. The sensitivity of cells overexpressing HOTAIR to two different types of human epidermal growth factor receptor 2 (HER2) inhibitors (trastuzumab and afatinib) showed that overexpression of HOTAIR is specific for trastuzumab resistance. Furthermore, luciferase reporter gene assay and western blot assay showed that there is a HOTAIR-miRNA330-ERBB4 competitive endogenous RNA regulatory network with miRNA330 as the core.

Conclusion: HOTAIR can not only promote tumor proliferation but also enhance the resistance of tumor cells to drugs. Our experimental data not only showed strong expression of HOTAIR in gastric cancer, but also that strong expression of HOTAIR caused the sensitivity of gastric cancer cells to trastuzumab, which is a useful reference for postoperative medication.

Keywords: Trastuzumab, HOTAIR, Afatinib, ERBB4, HER2, miRNA330, gastric cancers.

Graphical Abstract
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[] [PMID: 25220842]
Theuer, C.P.; Kurosaki, T.; Ziogas, A.; Butler, J.; Anton-Culver, H. Asian patients with gastric carcinoma in the United States exhibit unique clinical features and superior overall and cancer specific survival rates. Cancer, 2000, 89(9), 1883-1892.
[<1883:AID-CNCR3>3.3.CO;2-8] [PMID: 11064344]
Zhong, X. Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J. Clin. Oncol., 2009, 27(S18) LBA4509
Sutcliffe, J.G.; Foye, P.E.; Erlander, M.G.; Hilbush, B.S.; Bodzin, L.J.; Durham, J.T.; Hasel, K.W. TOGA: An automated parsing technology for analyzing expression of nearly all genes. Proc. Natl. Acad. Sci. USA, 2000, 97(5), 1976-1981.
[] [PMID: 10681428]
Rinn, J.L.; Kertesz, M.; Wang, J.K.; Squazzo, S.L.; Xu, X.; Brugmann, S.A.; Goodnough, L.H.; Helms, J.A.; Farnham, P.J.; Segal, E.; Chang, H.Y. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell, 2007, 129(7), 1311-1323.
[] [PMID: 17604720]
Woo, C.J.; Kingston, R.E. HOTAIR lifts noncoding RNAs to new levels. Cell, 2007, 129(7), 1257-1259.
[] [PMID: 17604716]
Gupta, R.A.; Shah, N.; Wang, K.C.; Kim, J.; Horlings, H.M.; Wong, D.J.; Tsai, M.C.; Hung, T.; Argani, P.; Rinn, J.L.; Wang, Y.; Brzoska, P.; Kong, B.; Li, R.; West, R.B.; van de Vijver, M.J.; Sukumar, S.; Chang, H.Y. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature, 2010, 464(7291), 1071-1076.
[] [PMID: 20393566]
Endo, H.; Shiroki, T.; Nakagawa, T.; Yokoyama, M.; Tamai, K.; Yamanami, H.; Fujiya, T.; Sato, I.; Yamaguchi, K.; Tanaka, N.; Iijima, K.; Shimosegawa, T.; Sugamura, K.; Satoh, K. Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer. PLoS One, 2013, 8(10) e77070
[] [PMID: 24130837]
Chisholm, K.M.; Wan, Y.; Li, R.; Montgomery, K.D.; Chang, H.Y.; West, R.B. Detection of long non-coding RNA in archival tissue: Correlation with polycomb protein expression in primary and metastatic breast carcinoma. PLoS One, 2012, 7(10) e47998
[] [PMID: 23133536]
Milhem, M.M.; Knutson, T.; Yang, S.; Zhu, D.; Wang, X.; Leslie, K.K.; Meng, X. Correlation of MTDH/AEG-1 and HOTAIR expression with metastasis and response to treatment in sarcoma patients J. Cancer Sci. Ther., 2011, S5((4)), 004.
[PMID: 23543869]
Li, D.; Feng, J.; Wu, T.; Wang, Y.; Sun, Y.; Ren, J.; Liu, M. Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma. Am. J. Pathol., 2013, 182(1), 64-70.
[] [PMID: 23141928]
Liao, A.; Liu, Z.; Lei, Z. The relationship study between the down expression of NDRG1 and E-cadherin with lymphonode metastasis in gastric cancer. J. Mol. Diagnostics Ther., 2015, 12(2), 176-179.
Dressler, F.; Whalen, J.A.; Reinhardt, B.N.; Steere, A.C. Western blotting in the serodiagnosis of lyme disease. J. Infect. Dis., 1993, 167(2), 392-400.
[] [PMID: 8380611]
Janku, F.; Wheler, J.J.; Westin, S.N.; Moulder, S.L.; Naing, A.; Tsimberidou, A.M.; Fu, S.; Falchook, G.S.; Hong, D.S.; Garrido-Laguna, I.; Luthra, R.; Lee, J.J.; Lu, K.H.; Kurzrock, R. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J. Clin. Oncol., 2012, 30(8), 777-782.
[] [PMID: 22271473]
Endo, H.; Shiroki, T.; Nakagawa, T.; Yokoyama, M.; Tamai, K. Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer. PLoS One, , 8(10) e77070
Xu, Z.Y.; Yu, Q.M.; Du, Y.A.; Yang, L.T.; Dong, R.Z.; Huang, L.; Yu, P.F.; Cheng, X.D. Knockdown of long non-coding RNA HOTAIR suppresses tumor invasion and reverses epithelial-mesenchymal transition in gastric cancer. Int. J. Biol. Sci., 2013, 9(6), 587-597.
[] [PMID: 23847441]
Wang, Y.; Wang, H.; Song, T.; Zou, Y.; Jiang, J.; Fang, L.; Li, P. HOTAIR is a potential target for the treatment of cisplatinresistant ovarian cancer. Mol. Med. Rep., 2015, 12(2), 2211-2216.
[] [PMID: 25824616]
Madarnas, Y.; Trudeau, M.; Franek, J.A.; McCready, D.; Pritchard, K.I.; Messersmith, H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: A systematic review. Cancer Treat. Rev., 2008, 34(6), 539-557.
[] [PMID: 18502589]
Elster, N.; Toomey, S.; Fan, Y.; Cremona, M.; Morgan, C.; Weiner Gorzel, K.; Bhreathnach, U.; Milewska, M.; Murphy, M.; Madden, S.; Naidoo, J.; Fay, J.; Kay, E.; Carr, A.; Kennedy, S.; Furney, S.; Mezynski, J.; Breathhnach, O.; Morris, P.; Grogan, L.; Hill, A.; Kennedy, S.; Crown, J.; Gallagher, W.; Hennessy, B.; Eustace, A. Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer. Ther. Adv. Med. Oncol., 2018, 101758835918778297
[] [PMID: 30023006]
Gunzer, K.; Joly, F.; Ferrero, J.M.; Gligorov, J.; de Mont-Serrat, H.; Uttenreuther-Fischer, M.; Pelling, K.; Wind, S.; Bousquet, G.; Misset, J.L. A phase II study of afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole. Springerplus, 2016, 5(1), 45.
[] [PMID: 26835225]
Lin, N.U.; Winer, E.P.; Wheatley, D.; Carey, L.A.; Houston, S.; Mendelson, D.; Munster, P.; Frakes, L.; Kelly, S.; Garcia, A.A.; Cleator, S.; Uttenreuther-Fischer, M.; Jones, H.; Wind, S.; Vinisko, R.; Hickish, T. A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res. Treat., 2012, 133(3), 1057-1065.
[] [PMID: 22418700]
Muraoka-Cook, R.S.; Feng, S.M.; Strunk, K.E.; Earp, H.S., III ErbB4/HER4: Role in mammary gland development, differentiation and growth inhibition. J. Mammary Gland Biol. Neoplasia, 2008, 13(2), 235-246.
[] [PMID: 18437540]
Bellinger, G. Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4. Oncogene, 2006, 25(41), 5664-5672.
Holbro, T.; Beerli, R.R.; Maurer, F.; Koziczak, M.; Barbas, C.F., III; Hynes, N.E. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl. Acad. Sci. USA, 2003, 100(15), 8933-8938.
[] [PMID: 12853564]
Liu, J.; Pan, C.; Guo, L.; Wu, M.; Guo, J.; Peng, S.; Wu, Q.; Zuo, Q. A new mechanism of trastuzumab resistance in gastric cancer: MACC1 promotes the Warburg effect via activation of the PI3K/AKT signaling pathway. J. Hematol. Oncol., 2016, 9(1), 76.
[] [PMID: 27581375]
Tang, L.; Long, Z.; Zhao, N.; Feng, G.; Guo, X.; Yu, M. NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer. J. Cell. Biochem., 2018, 119(8), 6398-6407.
[] [PMID: 29231994]

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