Tumor Biology

, Volume 37, Issue 1, pp 1079–1089 | Cite as

The long noncoding RNA, EGFR-AS1, a target of GHR, increases the expression of EGFR in hepatocellular carcinoma

  • Hao-long Qi
  • Chang-sheng Li
  • Chong-wei Qian
  • Yu-sha Xiao
  • Yu-feng Yuan
  • Quan-yan Liu
  • Zhi-su Liu
Original Article


LncRNA has provided an important new perspective regarding gene regulation. Both the expression and activation of EGFR have been proven to be under the tight control of the GHR pathway. EGFR-AS1 has been found to inhibit the expression of EGFR. GHR-siRNA and EGFR-AS1-siRNA were transfected into HCC cell lines, and a series of WB, q-PCR, and IF experiments was conducted to evaluate whether EGFR-AS1 participated in the regulation of GHR and EGFR. We found that impeded expression of GHR decreased the expression of EGFR and EGFR-AS1 in vivo and in vitro. Then, it was verified that EGFR and EGFR-AS1 were relatively upregulated in HCC tissue, and they were significantly related to some clinical characteristics and patient prognosis. Furthermore, EGFR-AS1 was determined to promote HCC development by improving the ability of invasion and proliferation of HCC cells in vitro, and it was also found to affect the cell cycle. Our study identified that EGFR-AS1 may promote HCC genesis and development. EGFR-AS1 may act as a prognostic factor in HCC. More importantly, we observed that the inhibition of EGFR-AS1 in HCC cells significantly impeded cell proliferation and invasion in vivo, which might provide a potential possibility for targeted therapy of HCC.


Growth hormone receptor Epidermal growth factor receptor Long noncoding RNA EGFR-AS1 Hepatocellular carcinoma 



We thank Prof. Wanyu’s generosity, which allowed our study to be conducted smoothly. This work was supported by the National Natural Science Foundation of China (No. 81172349 and No. 81272692).

Conflicts of interest



  1. 1.
    Verslype C. Hepatocellular carcinoma: ESMO–ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2012;23(Supplement 7):vii41–8.PubMedGoogle Scholar
  2. 2.
    Buckley AF, Burgart LJ, Sahai V, Kakar S. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am J Clin Pathol. 2008;129:245–51.CrossRefPubMedGoogle Scholar
  3. 3.
    Gozalez L et al. GH modulates hepatic epidermal growth factor signaling in the mouse. J Endorin. 2010;204:299–309.CrossRefGoogle Scholar
  4. 4.
    Zerrad-Saadi A et al. GH receptor plays a major role in liver regeneration through the control of EGFR and ERK1/2 activation. Endocrinology. 2011;152(7):2731–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2007;7:225–35.CrossRefGoogle Scholar
  6. 6.
    Brooks AJ, Wooh JW, Tunny KA, Waters MJ. Growth hormone receptor; mechanism of action. Int J Biochem Cell Biology. 2008;40:1984–9.CrossRefGoogle Scholar
  7. 7.
    Barclay JL et al. In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2. Mol Endocrinol. 2010;24:204–17.CrossRefPubMedGoogle Scholar
  8. 8.
    Huang Y et al. Growth hormone-induced phosphorylation of epidermal growth factor (EGF) receptor in 3T3-F442A cells. Modulation of EGF-induced trafficking and signaling. J Biological Chem. 2007;278:18902–13.CrossRefGoogle Scholar
  9. 9.
    Miquet JG et al. Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation. J Endocrin. 2008;198:317–30.CrossRefGoogle Scholar
  10. 10.
    Takahashi K et al. Long noncoding RNA in liver diseases. Hepatology. 2014;60(2):744–53.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Braconi C et al. Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci USA. 2011;108:786–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Kogure T et al. Extracellular vesicle mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes and Cancer. 2013;4:261–72.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Petch AK et al. Messenger RNA expression profiling of genes involved in epidermal growth factor receptor signalling in human cancer cells treated with scanning array-designed antisense oligonucleotides. Biochem Pharmacol. 2003;66(5):819–30.CrossRefPubMedGoogle Scholar
  14. 14.
    Hu G, Lou Z, Gupta M. The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation. PLoS One. 2014;9(9):e107016. doi: 10.1371/journal.pone.0107016.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Qiao HP et al. Long non-coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. Asian Pac J Cancer Prev. 2013;14:1077–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Lu X et al. Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell Tissue Res. 2013;354:891–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu Z et al. Downregulation of GAS5 promotes bladder cancer cell proliferation, partly by regulating CDK6. PLoS One. 2013;8:e73991.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    He E et al. Fractionated ionizing radiation promotes epithelial-mesenchymal transition in human esophageal cancer cells through PTEN deficiency-mediated Akt activation. PLoS One. 2015;10(5):e0126149. doi: 10.1371/journal.pone.0126149.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hassan H, Greve B, Pavao MS, Kiesel L, Ibrahim SA, Gotte M. Syndecan-1 modulates beta-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation. FEBS J. 2013;280(10):2216–27. doi: 10.1111/febs.12111.CrossRefPubMedGoogle Scholar
  20. 20.
    Theys J, Jutten B, Habets R, Paesmans K, Groot AJ, Lambin P, et al. E-cadherin loss associated with EMT promotes radioresistance in human tumor cells. Radiother Oncol. 2011;99(3):392–7. doi: 10.1016/j.radonc.2011.05.044S0167-8140(11)00237-4.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73. doi: 10.1038/nrc2620nrc2620.CrossRefPubMedGoogle Scholar
  22. 22.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8. doi: 10.1172/JCI3910439104.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Hao-long Qi
    • 1
  • Chang-sheng Li
    • 1
  • Chong-wei Qian
    • 1
  • Yu-sha Xiao
    • 1
  • Yu-feng Yuan
    • 1
  • Quan-yan Liu
    • 1
  • Zhi-su Liu
    • 1
  1. 1.Department of General Surgery, Research Center of Digestive Diseases, Zhongnan HospitalWuhan UniversityWuhanPeople’s Republic of China

Personalised recommendations