Tumor Biology

, Volume 37, Issue 2, pp 1683–1691 | Cite as

Long non-coding RNA MALAT1 modulates radiosensitivity of HR-HPV+ cervical cancer via sponging miR-145

  • Hongzhi Lu
  • Yu He
  • Lin Lin
  • Zhengqin Qi
  • Li Ma
  • Li Li
  • Ying SuEmail author
Original Article


Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA playing oncogenic role in several cancers, including cervical cancer. However, its role in radiosensitivity of cervical cancer is not yet well understood. This study explored the role of MALAT1 in radiosensitivity of high-risk human papillomavirus (HR-HPV)-positive cervical cancer and whether there is a ceRNA mechanism which participated in its regulation over radiosensitivity. Based on tissue samples from 50 cervical cancer cases and 25 healthy controls, we found MALAT1 expression was significantly higher in radioresistant than in radiosensitive cancer cases. In addition, MALAT1 and miR-145 expression inversely changed in response to irradiation in HR-HPV+ cervical cancer cells. By using clonogenic assay and flow cytometry analysis of cell cycle distribution and apoptosis, we found CaSki and Hela cells with knockdown of MALAT1 had significantly lower colony formation, higher ratio of G2/M phase block and higher ratio of cell apoptosis. By performing RNA-binding protein immunoprecipitation (RIP) assay and RNA pull-down assay, we confirmed that miR-145 and MALAT1 were in the same Ago2 complex and there was a reciprocal repression between them. Then, we explored the function of MALAT1-miR-145 in radiosensitivity of cervical cancers cells and demonstrated that si-MALAT1 and miR-145 had some level of synergic effect in reducing cancer cell colony formation, cell cycle regulation, and inducing apoptosis. These findings provide an important clue about microRNA-lncRNA interaction in the mechanism of radioresistance of cervical cancer.


lncRNA MALAT1 Cervical cancer HPV miR-145 Radiotherapy 


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a Cancer Journal for Clinicians. 2014;64:9–29.Google Scholar
  2. 2.
    Rogers L, Siu SS, Luesley D, Bryant A, Dickinson HO. Radiotherapy and chemoradiation after surgery for early cervical cancer. The Cochrane Database of Systematic Reviews. 2012;5, CD007583.PubMedCentralGoogle Scholar
  3. 3.
    Powell ME. Modern radiotherapy and cervical cancer. International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2010;20:S49–51.CrossRefGoogle Scholar
  4. 4.
    Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 2011;32:1697–705.CrossRefPubMedGoogle Scholar
  5. 5.
    Lando M, Holden M, Bergersen LC, Svendsrud DH, Stokke T, Sundfor K, et al. Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer. PLoS Genetics. 2009;5, e1000719.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Molecular Cancer. 2011;10:38.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discovery. 2011;1:391–407.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gibb EA, Becker-Santos DD, Enfield KS, Guillaud M, Niekerk D, Matisic JP, et al. Aberrant expression of long noncoding RNAs in cervical intraepithelial neoplasia. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society. 2012;22:1557–63.CrossRefGoogle Scholar
  9. 9.
    Yin DD, Liu ZJ, Zhang E, Kong R, Zhang ZH, Guo RH. Decreased expression of long noncoding RNA MEG3 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2015;36:4851–9.CrossRefGoogle Scholar
  10. 10.
    Sun M, Xia R, Jin F, Xu T, Liu Z, De W, et al. Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2014;35:1065–73.CrossRefGoogle Scholar
  11. 11.
    Ying L, Huang Y, Chen H, Wang Y, Xia L, Chen Y, et al. Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer. Molecular BioSystems. 2013;9:407–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Qin R, Chen Z, Ding Y, Hao J, Hu J, Guo F. Long non-coding RNA MEG3 inhibits the proliferation of cervical carcinoma cells through the induction of cell cycle arrest and apoptosis. Neoplasma. 2013;60:486–92.CrossRefPubMedGoogle Scholar
  13. 13.
    Jiang Y, Li Y, Fang S, Jiang B, Qin C, Xie P, et al. The role of MALAT1 correlates with HPV in cervical cancer. Oncology Letters. 2014;7:2135–41.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Liu S, Song L, Zeng S, Zhang L. MALAT1-miR-124-RBG2 axis is involved in growth and invasion of HR-HPV-positive cervical cancer cells. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2015.Google Scholar
  15. 15.
    Zhang J, Wang L, Li B, Huo M, Mu M, Liu J, et al. miR-145 downregulates the expression of cyclin-dependent kinase 6 in human cervical carcinoma cells. Experimental and Therapeutic Medicine. 2014;8:591–4.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Chang S, Gao L, Yang Y, Tong D, Guo B, Liu L, et al. miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget. 2015;6:7675–85.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Qiu T, Zhou X, Wang J, Du Y, Xu J, Huang Z, et al. MiR-145, miR-133a and miR-133b inhibit proliferation, migration, invasion and cell cycle progression via targeting transcription factor Sp1 in gastric cancer. FEBS Letters. 2014;588:1168–77.CrossRefPubMedGoogle Scholar
  18. 18.
    Koh WJ, Greer BE, Abu-Rustum NR, Apte SM, Campos SM, Chan J, et al. National Comprehensive Cancer Network: cervical cancer. Journal of the National Comprehensive Cancer Network: JNCCN. 2013;11:320–43.CrossRefPubMedGoogle Scholar
  19. 19.
    Liu Q, Huang J, Zhou N, Zhang Z, Zhang A, Lu Z, et al. LncRNA loc285194 is a p53-regulated tumor suppressor. Nucleic Acids Research. 2013;41:4976–87.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zhang A, Zhou N, Huang J, Liu Q, Fukuda K, Ma D, et al. The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage. Cell Research. 2013;23:340–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005;123:631–40.CrossRefPubMedGoogle Scholar
  22. 22.
    Karginov FV, Conaco C, Xuan Z, Schmidt BH, Parker JS, Mandel G, et al. A biochemical approach to identifying microRNA targets. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:19291–6.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Research. 2013;73:1180–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Ji Q, Zhang L, Liu X, Zhou L, Wang W, Han Z, et al. Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex. British Journal of Cancer. 2014;111:736–48.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang J, Su L, Chen X, Li P, Cai Q, Yu B, et al. MALAT1 promotes cell proliferation in gastric cancer by recruiting SF2/ASF. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2014;68:557–64.CrossRefGoogle Scholar
  26. 26.
    Yang F, Yi F, Han X, Du Q, Liang Z. MALAT-1 interacts with hnRNP C in cell cycle regulation. FEBS Letters. 2013;587:3175–81.CrossRefPubMedGoogle Scholar
  27. 27.
    Wang X, Li M, Wang Z, Han S, Tang X, Ge Y, et al. Silencing of long noncoding RNA MALAT1 by miR-101 and miR-217 inhibits proliferation, migration, and invasion of esophageal squamous cell carcinoma cells. The Journal of Biological Chemistry. 2015;290:3925–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Bandopadhyay M, Banerjee A, Sarkar N, Panigrahi R, Datta S, Pal A, et al. Tumor suppressor micro RNA miR-145 and onco micro RNAs miR-21 and miR-222 expressions are differentially modulated by hepatitis B virus X protein in malignant hepatocytes. BMC Cancer. 2014;14:721.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Eades G, Wolfson B, Zhang Y, Li Q, Yao Y, Zhou Q. LincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Molecular cancer research: MCR. 2015;13:330–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Shen H, Shen J, Wang L, Shi Z, Wang M, Jiang BH, et al. Low miR-145 expression level is associated with poor pathological differentiation and poor prognosis in non-small cell lung cancer. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2015;69:301–5.CrossRefGoogle Scholar
  31. 31.
    Chang, S., Gao, L., Yang, Y., Tong, D., Guo, B., Liu, L., Li, Z., Song, T., and Huang C. 2015. miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget.Google Scholar
  32. 32.
    Xue G, Ren Z, Chen Y, Zhu J, Du Y, Pan D, et al. A feedback regulation between miR-145 and DNA methyltransferase 3b in prostate cancer cell and their responses to irradiation. Cancer Letters. 2015;361:121–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Shi M, Du L, Liu D, Qian L, Hu M, Yu M, et al. Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells. The Journal of Pathology. 2012;228:148–57.CrossRefPubMedGoogle Scholar
  34. 34.
    Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Hongzhi Lu
    • 1
  • Yu He
    • 2
  • Lin Lin
    • 3
  • Zhengqin Qi
    • 4
  • Li Ma
    • 1
  • Li Li
    • 1
  • Ying Su
    • 5
    Email author
  1. 1.Department of Infectious DiseaseThe First Hospital of QinhuangdaoQinhuangdaoChina
  2. 2.Gastroscopy RoomThe Central Hospital of ChengdeChengdeChina
  3. 3.Department of GynecologyThe First Hospital of QinhuangdaoQinhuangdaoChina
  4. 4.B-ultrasound RoomThe First Hospital of QinhuangdaoQinhuangdaoChina
  5. 5.Pediatric Intensive Care UnitThe First Hospital of QinhuangdaoQinhuangdaoChina

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