Tumor Biology

, Volume 37, Issue 9, pp 12061–12070 | Cite as

MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer

  • Yan-Ran Wu
  • Hai-Jun Qi
  • Dan-Fang Deng
  • Ying-Ying Luo
  • Sheng-Lan YangEmail author
Original Article


Our study aimed to explore associations between microRNA-21 (miR-21) and PTEN/PI3K/AKT signaling pathway and, further, to elucidate the regulation of miR-21 on biological behaviors in human esophageal cancer cells. The expressions of miR-21, PTEN, PI3K, and AKT were detected in 89 esophageal cancer samples and 58 adjacent normal tissues respectively. The human esophageal cancer cells (TE11) were grouped as following: blank (TE11 cells without transfection), negative (TE11 cells with miR-21 negative inhibitor), and Inhibition-miR21 (TE11 cells with miR-21 inhibitor). Western blot was used for detection of PTEN, P13K, and AKT protein expressions, MTT method for cell proliferation, Transwell assay for cell migration and invasion, and flow cytometry for cell cycle and apoptosis. MiR-21, PI3K, and AKT have higher expressions, but PTEN has lower expression in esophageal cancer tissues compared with adjacent normal tissues. The esophageal cancer tissues with lymph node metastasis and poor differentiation showed significantly low positive rate of PTEN protein, but high positive rates of PI3K and AKT proteins. Compared with blank and negative groups, PTEN expression of TE11 cells in Inhibition-miR21 group was significantly up-regulated, but PI3K and AKT were down-regulated. Further, PTEN was a target gene of miR-21. Besides, compared with blank and negative groups, the proliferation, migration, and invasion of TE11 cells were less active in Inhibition-miR21 group. TE11 cells were significantly increased in the G0/G1 phase of cell cycles, but decreased in the S and G2/M phase in Inhibition-miR21 group. The TE11 cells exhibited significantly increased apoptosis rates. MiR-21 targets key proteins in PTEN/PI3K/AKT signal pathway, promoting proliferation, migration, invasion, and cell cycle, and inhibiting apoptosis of human esophageal cancer cells. It may serve as a novel therapeutic target in esophageal cancer.


Esophageal cancer microRNA-21 PTEN/PI3K/AKT signal pathway Cell cycle Apoptosis 



We would like to acknowledge the helpful comments from our reviewers on this paper.

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Zhang SK, Guo LW, Chen Q, Zhang M, Liu SZ, Quan PL, et al. The association between human papillomavirus 16 and esophageal cancer in Chinese population: a meta-analysis. BMC Cancer. 2015;15:1096.PubMedGoogle Scholar
  2. 2.
    Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X, et al. Annual report on status of cancer in China, 2010. Chin J Cancer Res. 2014;26(1):48–58.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Fedotovskikh GV, Potapov VA. [Clinico-morphological evaluation of pathogenetic mechanisms of bouginage and intubation on cicatricial esophageal stenosis after chemical burns]. Grud Serdechnososudistaia Khir 1990 (10):65–8.Google Scholar
  4. 4.
    Scarpa M, Cavallin F, Saadeh LM, Pinto E, Alfieri R, Cagol M, et al. Hybrid minimally invasive esophagectomy for cancer: impact on postoperative inflammatory and nutritional status. Dis Esophagus. 2015. doi: 10.1111/dote.12418.Google Scholar
  5. 5.
    Song B, Cui H, Li Y, Cheng C, Yang B, Wang F, et al. Mutually exclusive mutations in notch1 and pik3ca associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China. Oncotarget. 2015;7:3599–613.PubMedCentralGoogle Scholar
  6. 6.
    Horna Strand A, Franzen T. Influence of life style factors on Barrett’s oesophagus. Gastroenterol Res Pract. 2014;2014:408470.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kobayashi R, Yamashita H, Okuma K, Shiraishi K, Ohtomo K, Nakagawa K. Salvage radiation therapy and chemoradiation therapy for postoperative locoregional recurrence of esophageal cancer. Dis Esophagus. 2014;27(1):72–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Sugimura K, Miyata H, Tanaka K, Takahashi T, Kurokawa Y, Yamasaki M, et al. High infiltration of tumor-associated macrophages is associated with a poor response to chemotherapy and poor prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer. J Surg Oncol. 2015;111(6):752–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Dvoretskii S, Levchenko EV, Karachun AM, Komarov IV, Pelipas’ Iu V, Avanesian AA, et al. [Experience of the use of endovideotechnology in surgical treatment of esophageal cancer]. Vestn Khir Im I I Grek. 2014;173(6):54–9.PubMedGoogle Scholar
  10. 10.
    Liu X, Liu Z, Hou W, Wang K, Ding W, Chen D, et al. [Changes in mitochondria fusion protein-2 hepatic expression in conditions of liver cirrhosis and acute on chronic liver failure]. Zhonghua Gan Zang Bing Za Zhi. 2014;22(9):671–5.PubMedGoogle Scholar
  11. 11.
    Yang Z, Fang S, Di Y, Ying W, Tan Y, Gu W. Modulation of nf-kappab/mir-21/pten pathway sensitizes non-small cell lung cancer to cisplatin. PLoS One. 2015;10(3):e0121547.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kar S, Samii A, Bertalanffy H. Pten/pi3k/akt/vegf signaling and the cross talk to krit1, ccm2, and pdcd10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015;38(2):229–36. discussion 36–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Wang J, Zhang C, Chen K, Tang H, Tang J, Song C, et al. Erbeta1 inversely correlates with pten/pi3k/akt pathway and predicts a favorable prognosis in triple-negative breast cancer. Breast Cancer Res Treat. 2015;152(2):255–69.CrossRefPubMedGoogle Scholar
  14. 14.
    de la Chapelle A, Jazdzewski K. Micrornas in thyroid cancer. J Clin Endocrinol Metab. 2011;96(11):3326–36.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bertrand FE, McCubrey JA, Angus CW, Nutter JM, Sigounas G. Notch and pten in prostate cancer. Adv Biol Regul. 2014;56:51–65.CrossRefPubMedGoogle Scholar
  16. 16.
    Kloosterman WP, Plasterk RH. The diverse functions of micrornas in animal development and disease. Dev Cell. 2006;11(4):441–50.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang Z, Li Z, Gao C, Chen P, Chen J, Liu W, et al. Mir-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Investig. 2008;88(12):1358–66.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH. Microrna-21 (mir-21) represses tumor suppressor pten and promotes growth and invasion in non-small cell lung cancer (nsclc). Clin Chim Acta. 2010;411(11–12):846–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. Mir-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803.CrossRefPubMedGoogle Scholar
  20. 20.
    Yan-nan B, Zhao-yan Y, Li-xi L, Jiang Y, Qing-jie X, Yong Z. Microrna-21 accelerates hepatocyte proliferation in vitro via pi3k/akt signaling by targeting pten. Biochem Biophys Res Commun. 2014;443(3):802–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Hong L, Han Y, Zhang Y, Zhang H, Zhao Q, Wu K, et al. Microrna-21: a therapeutic target for reversing drug resistance in cancer. Expert Opin Ther Targets. 2013;17(9):1073–80.CrossRefPubMedGoogle Scholar
  22. 22.
    Mastroleo I. Post-trial obligations in the declaration of helsinki 2013: classification, reconstruction and interpretation. Dev World Bioeth 2015.Google Scholar
  23. 23.
    Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H, et al. Coexpression of inducible nitric oxide synthase and cox-2 in hepatocellular carcinoma and surrounding liver: possible involvement of cox-2 in the angiogenesis of hepatitis c virus-positive cases. Clin Cancer Res. 2001;7(5):1325–32.PubMedGoogle Scholar
  24. 24.
    Ying J, Xu Q, Liu B, Zhang G, Chen L, Pan H. The expression of the pi3k/akt/mtor pathway in gastric cancer and its role in gastric cancer prognosis. Oncol Targets Ther. 2015;8:2427–33.CrossRefGoogle Scholar
  25. 25.
    Li P, Mao WM, Zheng ZG, Dong ZM, Ling ZQ. Down-regulation of pten expression modulated by dysregulated mir-21 contributes to the progression of esophageal cancer. Dig Dis Sci. 2013;58(12):3483–93.CrossRefPubMedGoogle Scholar
  26. 26.
    Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, et al. Microrna expression profiling in human ovarian cancer: Mir-214 induces cell survival and cisplatin resistance by targeting pten. Cancer Res. 2008;68(2):425–33.CrossRefPubMedGoogle Scholar
  27. 27.
    Xu LF, Wu ZP, Chen Y, Zhu QS, Hamidi S, Navab R. Microrna-21 (mir-21) regulates cellular proliferation, invasion, migration, and apoptosis by targeting pten, reck and bcl-2 in lung squamous carcinoma, Gejiu city, China. PLoS One. 2014;9(8):e103698.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hong Q, Yu S, Geng X, Duan L, Zheng W, Fan M, et al. High concentrations of uric acid inhibit endothelial cell migration via mir-663 which regulates phosphatase and tensin homolog by targeting transforming growth factor-beta1. Microcirculation. 2015;22(4):306–14.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Yan-Ran Wu
    • 1
  • Hai-Jun Qi
    • 2
  • Dan-Fang Deng
    • 1
  • Ying-Ying Luo
    • 1
  • Sheng-Lan Yang
    • 1
    Email author
  1. 1.Integrated TCM & Western MedicineUnion Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
  2. 2.Cardiovascular MedicineWuhan Central Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina

Personalised recommendations