Molecular and Cellular Biochemistry

, Volume 460, Issue 1–2, pp 1–8 | Cite as

LncRNA H19 promotes lung cancer proliferation and metastasis by inhibiting miR-200a function

  • Yi Zhao
  • Changjiang Feng
  • Yunjing Li
  • Yongfu MaEmail author
  • Ruijun CaiEmail author


Lung cancer is the major cause leading to cancer mortality, and the 5-year survival rate for patients with lung cancer still remains low. It is urgent to fully understand the development and progression of lung cancer to discover new therapeutic targets and develop new therapeutic approaches. H19 was documented to be upregulated in lung cancer and related to cell proliferation. However, it is still unclear if H19 has other functions in lung cancer. The mRNA levels of genes were detected by qRT-PCR, and the cell proliferation rate and cell viability were measured through cell count assay and MTT assay. Transwell assays were applied to detect cell abilities to migration and invasion, while luciferase reporter assay and RNA pull-down assay were used to examine interaction between H19 and miR-200a. H19 expression was elevated in the lung cancer tissues and cell lines, while H19 overexpression promoted the lung cancer cell growth, cell migration and invasion, as well as the epithelial mesenchymal transition (EMT). Meantime, RNA pull-down assay showed that H19 interacted with miR-200a, and miR-200a inhibited the activity of H19-fused luciferase. Furthermore, H19 overexpression inhibited miR-200a function and thereby upregulated miR-200a target genes, ZEB1 and ZEB2.H19 sponged and inhibited miR-200a to de-repress expression of ZEB1 and ZEB2, and thereby enhanced lung cancer proliferation and metastasis.


H19 miR-200a Lung cancer Proliferation Metastasis 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human and/or animal rights

This study had been approved by The Human Research Ethics Committee of the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University.

Informed consent

Written consents were derived from the participants.

Supplementary material

11010_2019_3564_MOESM1_ESM.pdf (98 kb)
Supplementary material 1 (PDF 97 kb)


  1. 1.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. CrossRefPubMedGoogle Scholar
  2. 2.
    Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, Kunkler I, Group E-W (2007) Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol 8:784–796. CrossRefPubMedGoogle Scholar
  3. 3.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30. CrossRefGoogle Scholar
  4. 4.
    Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, Willbanks A, Sarkar S (2015) EMT and tumor metastasis. Clin Transl Med 4:6. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sudo T, Iwaya T, Nishida N, Sawada G, Takahashi Y, Ishibashi M, Shibata K, Fujita H, Shirouzu K, Mori M, Mimori K (2013) Expression of mesenchymal markers vimentin and fibronectin: the clinical significance in esophageal squamous cell carcinoma. Ann Surg Oncol 20(Suppl 3):S324–335. CrossRefPubMedGoogle Scholar
  6. 6.
    Ayers D, Vandesompele J (2017) Influence of microRNAs and long non-coding RNAs in cancer chemoresistance. Genes (Basel). CrossRefGoogle Scholar
  7. 7.
    Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62. CrossRefPubMedGoogle Scholar
  8. 8.
    Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Brannan CI, Dees EC, Ingram RS, Tilghman SM (1990) The product of the H19 gene may function as an RNA. Mol Cell Biol 10:28–36CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kondo M, Suzuki H, Ueda R, Osada H, Takagi K, Takahashi T, Takahashi T (1995) Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene 10:1193–1198PubMedGoogle Scholar
  11. 11.
    Mizrahi A, Czerniak A, Levy T, Amiur S, Gallula J, Matouk I, Abu-lail R, Sorin V, Birman T, de Groot N, Hochberg A, Ohana P (2009) Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences. J Transl Med 7:69. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Nakagawa H, Chadwick RB, Peltomaki P, Plass C, Nakamura Y, de La Chapelle A (2001) Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci USA 98:591–596. CrossRefPubMedGoogle Scholar
  13. 13.
    Collette J, Le Bourhis X, Adriaenssens E (2017) Regulation of human breast cancer by the long non-coding RNA H19. Int J Mol Sci. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Matouk IJ, Halle D, Raveh E, Gilon M, Sorin V, Hochberg A (2016) The role of the oncofetal H19 lncRNA in tumor metastasis: orchestrating the EMT-MET decision. Oncotarget 7:3748–3765. CrossRefPubMedGoogle Scholar
  15. 15.
    Yang Q, Wang X, Tang C, Chen X, He J (2017) H19 promotes the migration and invasion of colon cancer by sponging miR-138 to upregulate the expression of HMGA1. Int J Oncol 50:1801–1809. CrossRefPubMedGoogle Scholar
  16. 16.
    Zhou X, Ye F, Yin C, Zhuang Y, Yue G, Zhang G (2015) The interaction between MiR-141 and lncRNA-H19 in regulating cell proliferation and migration in gastric cancer. Cell Physiol Biochem 36:1440–1452. CrossRefPubMedGoogle Scholar
  17. 17.
    Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan DC, Zhang JF, Waye MM (2015) The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget 6:22513–22525. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Raveh E, Matouk IJ, Gilon M, Hochberg A (2015) The H19 Long non-coding RNA in cancer initiation, progression and metastasis—a proposed unifying theory. Mol Cancer 14:184. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Park IY, Sohn BH, Choo JH, Joe CO, Seong JK, Lee YI, Chung JH (2005) Deregulation of DNA methyltransferases and loss of parental methylation at the insulin-like growth factor II (Igf2)/H19 loci in p53 knockout mice prior to tumor development. J Cell Biochem 94:585–596. CrossRefPubMedGoogle Scholar
  21. 21.
    Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J, Fang G (2012) Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J 279:3159–3165. CrossRefPubMedGoogle Scholar
  22. 22.
    Matouk IJ, Mezan S, Mizrahi A, Ohana P, Abu-Lail R, Fellig Y, Degroot N, Galun E, Hochberg A (2010) The oncofetal H19 RNA connection: hypoxia, p53 and cancer. Biochim Biophys Acta 1803:443–451. CrossRefPubMedGoogle Scholar
  23. 23.
    Cancer Genome Atlas Research N (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–550. CrossRefGoogle Scholar
  24. 24.
    Lehman TA, Bennett WP, Metcalf RA, Welsh JA, Ecker J, Modali RV, Ullrich S, Romano JW, Appella E, Testa JR et al (1991) p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res 51:4090–4096PubMedGoogle Scholar
  25. 25.
    Cui J, Mo J, Luo M, Yu Q, Zhou S, Li T, Zhang Y, Luo W (2015) c-Myc-activated long non-coding RNA H19 downregulates miR-107 and promotes cell cycle progression of non-small cell lung cancer. Int J Clin Exp Pathol 8:12400–12409PubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang E, Li W, Yin D, De W, Zhu L, Sun S, Han L (2016) c-Myc-regulated long non-coding RNA H19 indicates a poor prognosis and affects cell proliferation in non-small-cell lung cancer. Tumour Biol 37:4007–4015. CrossRefPubMedGoogle Scholar
  27. 27.
    Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, Lu L, Liu C, Yi JS, Zhang H, Min W, Bennett AM, Gregory RI, Ding Y, Huang Y (2013) The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell 52:101–112. CrossRefPubMedGoogle Scholar
  28. 28.
    Ma C, Nong K, Zhu H, Wang W, Huang X, Yuan Z, Ai K (2014) H19 promotes pancreatic cancer metastasis by derepressing let-7′s suppression on its target HMGA2-mediated EMT. Tumour Biol 35:9163–9169. CrossRefPubMedGoogle Scholar
  29. 29.
    Monnier P, Martinet C, Pontis J, Stancheva I, Ait-Si-Ali S, Dandolo L (2013) H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1. Proc Natl Acad Sci USA 110:20693–20698. CrossRefPubMedGoogle Scholar
  30. 30.
    Chang CJ, Hung MC (2012) The role of EZH2 in tumour progression. Br J Cancer 106:243–247. CrossRefPubMedGoogle Scholar
  31. 31.
    Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J (2013) Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett 333:213–221. CrossRefPubMedGoogle Scholar
  32. 32.
    Tsouko E, Wang J, Frigo DE, Aydogdu E, Williams C (2015) miR-200a inhibits migration of triple-negative breast cancer cells through direct repression of the EPHA2 oncogene. Carcinogenesis 36:1051–1060. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Eades G, Yang M, Yao Y, Zhang Y, Zhou Q (2011) miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem 286:40725–40733. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yoneyama K, Ishibashi O, Kawase R, Kurose K, Takeshita T (2015) miR-200a, miR-200b and miR-429 are onco-miRs that target the PTEN gene in endometrioid endometrial carcinoma. Anticancer Res 35:1401–1410PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Thoracic Surgery, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
  2. 2.Department of Thoracic SurgeryPLA General HospitalBeijingChina

Personalised recommendations