LncRNA HEIH Enhances Paclitaxel-Tolerance of Endometrial Cancer Cells via Activation of MAPK Signaling Pathway

Abstract

This study aimed to investigate the function of lncRNA HEIH on promoting endometrial cancer cells’ tolerance of paclitaxel (PTX). LncRNA HEIH expression was measured by QRT-PCR in endometrial cancer tissues, human healthy tissues and cell lines. The PTX-resistant endometrial cancer cells (Ishikawa-RE and HHUA-RE) were intermittently exposed to increase concentrations of PTX and were constructed as evidenced by MTT assay. Besides, the specific siRNA of HEIH (siHEIH) and pcDNA3.1-HEIH plasmid transfection were utilized to alter the expression of HEIH in the cells and investigate the effects of HEIH on resistance to PTX in endometrial cancer cells. Moreover, MTT, colony formation and apoptosis analysis were taken advantage to evaluate cell viability and proliferation when treated with PTX. Then, differential genes in PTX-resistant and HEIH-knock-down PTX-resistant endometrial cancer cells were screened out by microarray analysis. Finally, gene-set enrichment analysis was used to predict the promising signaling pathway of HEIH and western blotting analysis were performed to verify the relevant genes expression of MAPK signaling pathway. LncRNA HEIH, the dysregulation of which involved in production of drug-resistance, was overexpressed in PTX-resistant endometrial cancer cells. Up-regulating HEIH would activate MAPK pathway, promote chemo-resistance of endometrial cancer cells and enhance cell proliferation and viability, whereas silencing HEIH depressed the MAPK signaling pathway, contributed to restoring chemo-sensitivity to PTX and repressed cell physiological process. Down-regulating lncRNA HEIH expression reversed the PTX-resistance of endometrial cancer cells through MAPK signaling pathway.

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References

  1. 1.

    Dong L, Zhou Q, Zhang Z, Zhu Y, Duan T, Feng Y (2012) Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J Obstet Gynaecol Res 38(8):1077–1085. https://doi.org/10.1111/j.1447-0756.2011.01839.x

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kharma B, Baba T, Mandai M, Matsumura N, Murphy SK, Kang HS, Yamanoi K, Hamanishi J, Yamaguchi K, Yoshioka Y, Konishi I (2013) Utilization of genomic signatures to identify high-efficacy candidate drugs for chemorefractory endometrial cancers. Int J Cancer 133(9):2234–2244. https://doi.org/10.1002/ijc.28220

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Viswanathan AN, Moughan J, Miller BE, Xiao Y, Jhingran A, Portelance L, Bosch WR, Matulonis UA, Horowitz NS, Mannel RS, Souhami L, Erickson BA, Winter KA, Small W Jr, Gaffney DK (2015) NRG oncology/RTOG 0921: a phase 2 study of postoperative intensity-modulated radiotherapy with concurrent cisplatin and bevacizumab followed by carboplatin and paclitaxel for patients with endometrial cancer. Cancer 121(13):2156–2163. https://doi.org/10.1002/cncr.29337

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Galaal K, Al Moundhri M, Bryant A, Lopes AD, Lawrie TA (2014) Adjuvant chemotherapy for advanced endometrial cancer. Cochrane Database Syst Rev 5:CD010681. https://doi.org/10.1002/14651858.CD010681.pub2

    Article  Google Scholar 

  5. 5.

    Reyes HD, Miecznikowski J, Gonzalez-Bosquet J, Devor EJ, Zhang Y, Thiel KW, Samuelson MI, McDonald M, Stephan JM, Hanjani P, Guntupalli S, Tewari KS, Backes F, Ramirez N, Fleming GF, Filiaci V, Birrer MJ, Leslie KK (2017) High stathmin expression is a marker for poor clinical outcome in endometrial cancer: an NRG oncology group/gynecologic oncology group study. Gynecol Oncol 146(2):247–253. https://doi.org/10.1016/j.ygyno.2017.05.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Altundag O, Dursun P, Ayhan A (2010) Emerging drugs in endometrial cancers. Expert Opin Emerg Drugs 15(4):557–568. https://doi.org/10.1517/14728214.2010.517521

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Jiang SJ, Zhang S, Mu XY, Li W, Wang Y (2008) Effects of trichostatin a and paclitaxel on apoptosis and microtubule stabilization in endometrial carcinoma cells: an in vitro research. Zhonghua Yi Xue Za Zhi 88(34):2427–2431

    CAS  PubMed  Google Scholar 

  8. 8.

    Kuittinen T, Rovio P, Staff S, Luukkaala T, Kallioniemi A, Grenman S, Laurila M, Maenpaa J (2017) Paclitaxel, carboplatin and 1,25-D3 inhibit proliferation of endometrial cancer cells in vitro. Anticancer Res 37(12):6575–6581. https://doi.org/10.21873/anticanres.12114

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Liz J, Esteller M (2016) lncRNAs and microRNAs with a role in cancer development. Biochim Biophys Acta 1859(1):169–176. https://doi.org/10.1016/j.bbagrm.2015.06.015

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Philippen LE, Dirkx E, da Costa-Martins PA, De Windt LJ (2015) Non-coding RNA in control of gene regulatory programs in cardiac development and disease. J Mol Cell Cardiol 89(Pt A):51–58. https://doi.org/10.1016/j.yjmcc.2015.03.014

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Bawa P, Zackaria S, Verma M, Gupta S, Srivatsan R, Chaudhary B, Srinivasan S (2015) Integrative analysis of Normal long intergenic non-coding RNAs in prostate Cancer. PLoS One 10(5):e0122143. https://doi.org/10.1371/journal.pone.0122143

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Szafranski K, Abraham KJ, Mekhail K (2015) Non-coding RNA in neural function, disease, and aging. Front Genet 6:87. https://doi.org/10.3389/fgene.2015.00087

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Malek E, Kim BG, Driscoll JJ (2016) Identification of long non-coding RNAs deregulated in multiple myeloma cells resistant to proteasome inhibitors. Genes (Basel) 7(10). https://doi.org/10.3390/genes7100084

  14. 14.

    Liu S, Zou B, Tian T, Luo X, Mao B, Zhang X, Lei H (2018) Overexpression of the lncRNA FER1L4 inhibits paclitaxel tolerance of ovarian cancer cells via the regulation of the MAPK signaling pathway. J Cell Biochem. https://doi.org/10.1002/jcb.28032

  15. 15.

    Zhao H, Xing G, Wang Y, Luo Z, Liu G, Meng H (2017) Long noncoding RNA HEIH promotes melanoma cell proliferation, migration and invasion via inhibition of miR-200b/a/429. Biosci Rep 37(3). https://doi.org/10.1042/BSR20170682

  16. 16.

    Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, Zhu N, Zhou WP, Yang GS, Wang YZ, Shang JL, Gao CF, Zhang FR, Wang F, Sun SH (2011) Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology 54(5):1679–1689. https://doi.org/10.1002/hep.24563

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    He Y, Meng XM, Huang C, Wu BM, Zhang L, Lv XW, Li J (2014) Long noncoding RNAs: novel insights into hepatocelluar carcinoma. Cancer Lett 344(1):20–27. https://doi.org/10.1016/j.canlet.2013.10.021

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Haque SU, Niu L, Kuhnell D, Hendershot J, Biesiada J, Niu W, Hagan MC, Kelsey KT, Casper KA, Wise-Draper TM, Medvedovic M, Langevin SM (2018) Differential expression and prognostic value of long non-coding RNA in HPV-negative head and neck squamous cell carcinoma. Head Neck 40(7):1555–1564. https://doi.org/10.1002/hed.25136

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Cui C, Zhai D, Cai L, Duan Q, Xie L, Yu J (2018) Long noncoding RNA HEIH promotes colorectal cancer tumorigenesis via counteracting miR-939Mediated transcriptional repression of Bcl-xL. Cancer Res Treat 50(3):992–1008. https://doi.org/10.4143/crt.2017.226

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Zhang Y, Li Z, Zhang Y, Zhong Q, Chen Q, Zhang L (2015) Molecular mechanism of HEIH and HULC in the proliferation and invasion of hepatoma cells. Int J Clin Exp Med 8(8):12956–12962

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Tanaka T, Toujima S, Tanaka J (2012) Differential sensitivity to paclitaxel-induced apoptosis and growth suppression in paclitaxel-resistant cell lines established from HEC-1 human endometrial adenocarcinoma cells. Int J Oncol 41(5):1837–1844. https://doi.org/10.3892/ijo.2012.1600

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Li L, Shou H, Wang Q, Liu S (2019) Investigation of the potential theranostic role of KDM5B/miR-29c signaling axis in paclitaxel resistant endometrial carcinoma. Gene. https://doi.org/10.1016/j.gene.2018.12.076

  23. 23.

    Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, De W, Wang Z, Wang R (2013) The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One 8(10):e77293. https://doi.org/10.1371/journal.pone.0077293

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Wang Q, Zhang W, Hao S (2017) LncRNA CCAT1 modulates the sensitivity of paclitaxel in nasopharynx cancers cells via miR-181a/CPEB2 axis. Cell Cycle 16(8):795–801. https://doi.org/10.1080/15384101.2017.1301334

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gaundar SS, Bendall LJ (2010) The potential and limitations of p38MAPK as a drug target for the treatment of hematological malignancies. Curr Drug Targets 11(7):823–833

    CAS  Article  Google Scholar 

  26. 26.

    Noel JK, Crean S, Claflin JE, Ranganathan G, Linz H, Lahn M (2008) Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 mitogen-activated protein kinases for treatment of cancer. A systematic review of the literature. Med Oncol 25(3):323–330. https://doi.org/10.1007/s12032-008-9039-1

    Article  PubMed  Google Scholar 

  27. 27.

    Bai L, Mao R, Wang J, Ding L, Jiang S, Gao C, Kang H, Chen X, Sun X, Xu J (2015) ERK1/2 promoted proliferation and inhibited apoptosis of human cervical cancer cells and regulated the expression of c-Fos and c-Jun proteins. Med Oncol 32(3):57. https://doi.org/10.1007/s12032-015-0490-5

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Liu C, Ding L, Bai L, Chen X, Kang H, Hou L, Wang J (2017) Folate receptor alpha is associated with cervical carcinogenesis and regulates cervical cancer cells growth by activating ERK1/2/c-Fos/c-Jun. Biochem Biophys Res Commun 491(4):1083–1091. https://doi.org/10.1016/j.bbrc.2017.08.015

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    McGivern N, El-Helali A, Mullan P, McNeish IA, Paul Harkin D, Kennedy RD, McCabe N (2018) Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer. Oncotarget 9(4):4722–4736. https://doi.org/10.18632/oncotarget.23524

    Article  PubMed  Google Scholar 

  30. 30.

    Wang P, Chen D, Ma H, Li Y (2017) LncRNA SNHG12 contributes to multidrug resistance through activating the MAPK/slug pathway by sponging miR-181a in non-small cell lung cancer. Oncotarget 8(48):84086–84101. https://doi.org/10.18632/oncotarget.20475

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by New Bud Science Foundation(KX104), West China Second University Hospital, Sichuan University.

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JG, TT and JL: conception and design, analysis and interpretation of data; YY and LZ: drafting the article; YQ: revising it critically for important intellectual content. YQ is the guarantor.

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Correspondence to Yi Quan.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the committee of West China Second University Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Guo, JL., Tang, T., Li, JH. et al. LncRNA HEIH Enhances Paclitaxel-Tolerance of Endometrial Cancer Cells via Activation of MAPK Signaling Pathway. Pathol. Oncol. Res. 26, 1757–1766 (2020). https://doi.org/10.1007/s12253-019-00718-w

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Keywords

  • Endometrial cancer
  • HEIH
  • Paclitaxel resistance
  • MAPK signaling pathway