Tumor Biology

, Volume 36, Issue 5, pp 3611–3619 | Cite as

HOTAIR enhanced aggressive biological behaviors and induced radio-resistance via inhibiting p21 in cervical cancer

  • Li Jing
  • Wang Yuan
  • Dong Ruofan
  • Yu Jinjin
  • Qiu Haifeng
Research Article


We previously reported the frequent overexpression of HOX Antisense Intergenic RNA (HOTAIR) in human cervical cancer, which was significantly correlated with tumor progression and poor prognosis. In the present study, we investigated the detailed biological functions of HOTAIR in cervical cancer. In vitro, upregulation of HOTAIR inhibited apoptosis and promoted cellular proliferation, cell cycle progression, migration, and invasion; on the contrast, downregulation of HOTAIR induced more apoptosis, suppressed cellular proliferation, cell cycle, migration, and invasion. Moreover, a high level of HOTAIR was notably associated with radio-resistance and downregulation of p21 in the primary cultured cervical cancer cells. Further, we demonstrated that elevated HOTAIR could induce radio-resistance via inhibiting p21 in HeLa cells, while knockdown of HOTAIR upregulated p21 and consequentially increased the radio-sensitivity of C33A cells. Consistently, stable knockdown of HOTAIR significantly suppressed tumor growth and sensitized cervical cancer to radiotherapy in vivo. In conclusion, HOTAIR served as an onco-lncRNA in cervical cancer which could enhance various aggressive biological behaviors. Moreover, we proved that HOTAIR execute its functions mainly through inhibiting the p21 expression. These results proposed that targeting HOTAIR might be a potent therapeutic strategy in cervical cancer, especially for those patients who accepted radiotherapy.


Cervical cancer HOTAIR p21 Cell cycle Radio-resistance 



Our study was supported by grants from the Scientific Bureau of Wuxi (CSE31N1418) and the Health Bureau of Wuxi (MS201417, FYKY201401) to Yuan Wang.

Conflicts of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2011;127:2893–917.CrossRefGoogle Scholar
  3. 3.
    Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129:1311–23.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lu L, Zhu G, Zhang C, Deng Q, Katsaros D, Mayne ST, et al. Association of large noncoding RNA HOTAIR expression and its downstream intergenic CpG island methylation with survival in breast cancer. Breast Cancer Res Treat. 2012;136:875–83.CrossRefPubMedGoogle Scholar
  7. 7.
    Liu XH, Liu ZL, Sun M, Liu J, Wang ZX, De W. The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer. 2013;13:464.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sorensen KP, Thomassen M, Tan Q, Bak M, Cold S, Burton M, et al. Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat. 2013;142:529–36.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616–25.CrossRefPubMedGoogle Scholar
  10. 10.
    Hajjari M, Behmanesh M, Sadeghizadeh M, Zeinoddini M. Up-regulation of HOTAIR long non-coding RNA in human gastric adenocarcinoma tissues. Med Oncol. 2013;30:670.CrossRefPubMedGoogle Scholar
  11. 11.
    Ishibashi M, Kogo R, Shibata K, Sawada G, Takahashi Y, Kurashige J, et al. Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma. Oncol Rep. 2013;29:946–50.PubMedGoogle Scholar
  12. 12.
    Xu ZY, Yu QM, Du YA, Yang LT, Dong RZ, Huang L, et al. Knockdown of long non-coding RNA HOTAIR suppresses tumor invasion and reverses epithelial-mesenchymal transition in gastric cancer. Int J Biol Sci. 2013;9:587–97.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Padua Alves C, Fonseca AS, Muys BR, de Barros ELBR, Burger MC, de Souza JE, et al. Brief report: the lincRNA Hotair is required for epithelial-to-mesenchymal transition and stemness maintenance of cancer cell lines. Stem Cells. 2013;31:2827–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H, Takamaru H, et al. Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Res. 2012;72:1126–36.CrossRefPubMedGoogle Scholar
  15. 15.
    Li L, Liu B, Wapinski OL, Tsai MC, Qu K, Zhang J, et al. Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Reports. 2013;5:3–12.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Li D, Feng J, Wu T, Wang Y, Sun Y, Ren J, et al. Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma. Am J Pathol. 2013;182:64–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Ding C, Cheng S, Yang Z, Lv Z, Xiao H, Du C, et al. Long non-coding RNA HOTAIR promotes cell migration and invasion via down-regulation of RNA binding motif protein 38 in hepatocellular carcinoma cells. Int J Mol Sci. 2014;15:4060–76.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, et al. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One. 2013;8:e77293.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Carrion K, Dyo J, Patel V, Sasik R, Mohamed SA, Hardiman G, et al. The long non-coding HOTAIR is modulated by cyclic stretch and WNT/beta-CATENIN in human aortic valve cells and is a novel repressor of calcification genes. PLoS One. 2014;9:e96577.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yang G, Zhang S, Gao F, Liu Z, Lu M, Peng S, et al. Osteopontin enhances the expression of HOTAIR in cancer cells via IRF1. Biochim Biophys Acta. 1839;2014:837–48.Google Scholar
  21. 21.
    Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, et al. MiR-7, inhibited indirectly by LincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells 2014.Google Scholar
  22. 22.
    Qiu JJ, Lin YY, Ye LC, Ding JX, Feng WW, Jin HY, et al. Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer. Gynecol Oncol. 2014;134:121–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Li J, Wang Y, Yu J, Dong R, Qiu H. A high level of circulating HOTAIR is associated with progression and poor prognosis of cervical cancer. Tumour Biol. 2014.Google Scholar
  25. 25.
    Yuan W, Xiaoyun H, Haifeng Q, Jing L, Weixu H, Ruofan D, et al. MicroRNA-218 enhances the radiosensitivity of human cervical cancer via promoting radiation induced apoptosis. Int J Med Sci. 2014;11:691–6.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Endo H, Shiroki T, Nakagawa T, Yokoyama M, Tamai K, Yamanami H, et al. Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer. PLoS One. 2013;8:e77070.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
  28. 28.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  29. 29.
    Kesic V, Poljak M, Rogovskaya S. Cervical cancer burden and prevention activities in Europe. Cancer Epidemiol Biomarkers Prev. 2012;21:1423–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Garland SM, Bhatla N, Ngan HY. Cervical cancer burden and prevention strategies: Asia Oceania perspective. Cancer Epidemiol Biomarkers Prev. 2012;21:1414–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Yee GP, de Souza P, Khachigian LM. Current and potential treatments for cervical cancer. Curr Cancer Drug Targets. 2013;13:205–20.CrossRefPubMedGoogle Scholar
  32. 32.
    Banerjee R, Kamrava M. Brachytherapy in the treatment of cervical cancer: a review. Int J Women Health. 2014;6:555–64.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Li Jing
    • 1
    • 2
  • Wang Yuan
    • 3
  • Dong Ruofan
    • 3
  • Yu Jinjin
    • 3
  • Qiu Haifeng
    • 2
    • 4
  1. 1.Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  2. 2.Institute of Clinical MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  3. 3.Department of Obstetrics and GynecologyThe Affiliated Hospital of Jiangnan University and The 4th People’s Hospital of WuxiWuxiChina
  4. 4.Department of Obstetrics and GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina

Personalised recommendations