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

  • Jun-Liang Guo
  • Tian Tang
  • Jin-Hong Li
  • Yi-Hong Yang
  • Long Zhang
  • Yi QuanEmail author
Original Article


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.


Endometrial cancer HEIH Paclitaxel resistance MAPK signaling pathway 


Author Contributions

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.

Funding Information

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

Compliance with Ethical Standards

Ethical Approval

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.

Informed Consent

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

Conflict of Interest

The authors declare that they have no conflict of interest.


  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. CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefGoogle 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. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Altundag O, Dursun P, Ayhan A (2010) Emerging drugs in endometrial cancers. Expert Opin Emerg Drugs 15(4):557–568. CrossRefPubMedGoogle 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):2427–2431PubMedGoogle 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. CrossRefPubMedGoogle Scholar
  9. 9.
    Liz J, Esteller M (2016) lncRNAs and microRNAs with a role in cancer development. Biochim Biophys Acta 1859(1):169–176. CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Szafranski K, Abraham KJ, Mekhail K (2015) Non-coding RNA in neural function, disease, and aging. Front Genet 6:87. CrossRefPubMedPubMedCentralGoogle 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). CrossRefGoogle Scholar
  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. CrossRefGoogle Scholar
  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).
  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. CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedGoogle 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):12956–12962PubMedPubMedCentralGoogle 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. CrossRefPubMedGoogle 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. CrossRefGoogle Scholar
  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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedPubMedCentralGoogle 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):823–833CrossRefGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2019

Authors and Affiliations

  1. 1.Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of EducationSichuan UniversityChengdu CityPeople’s Republic of China

Personalised recommendations