Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines

  • Wang, Yong-Sheng (Department of Oncology, Shanghai Pulmonary Hospital, Tongji University) ;
  • Wang, Yin-Hua (Department of Oncology, The Second People's Hospital of Wuhu City, Wannan Medical College) ;
  • Xia, Hong-Ping (Department of Chemistry, University of Hong Kong) ;
  • Zhou, Song-Wen (Department of Oncology, Shanghai Pulmonary Hospital, Tongji University) ;
  • Schmid-Bindert, Gerald (Department of Interdisciplinary Thoracic Oncology, University Medical Center Mannheim, Heidelberg University) ;
  • Zhou, Cai-Cun (Department of Oncology, Shanghai Pulmonary Hospital, Tongji University)
  • Published : 2012.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)-namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto-oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy.

Keywords

References

  1. Bartel DP (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136, 215-33. https://doi.org/10.1016/j.cell.2009.01.002
  2. Bean J, Brennan C, Shih JY, et al (2007). MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA, 104, 20932-7. https://doi.org/10.1073/pnas.0710370104
  3. Blower PE, Chung JH, Verducci JS, et al. (2008). MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther, 7, 1-9. https://doi.org/10.1158/1535-7163.MCT-07-0573
  4. Derfoul, A, Juan AH, Difilippantonio MJ, et al (2011). Decreased microRNA-214 levels in breast cancer cells coincides with increased cell proliferation, invasion and accumulation of the Polycomb Ezh2 methyltransferase. Carcinogenesis, 32, 1607-14. https://doi.org/10.1093/carcin/bgr184
  5. Engelman JA, Mukohara T, Zejnullahu K, et al (2006). Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest, 116, 2695-706. https://doi.org/10.1172/JCI28656
  6. Engelman JA, Zejnullahu K, Mitsudomi T, et al. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science, 316, 1039-43. https://doi.org/10.1126/science.1141478
  7. Esquela-Kerscher A, Slack FJ (2006). Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer, 6, 259-69. https://doi.org/10.1038/nrc1840
  8. Fu YF, Du TT, Dong M, et al (2009). Mir-144 selectively regulates embryonic ${\alpha}$-hemoglobin synthesis during primitive erythropoiesis. Blood, 113, 1340-9. https://doi.org/10.1182/blood-2008-08-174854
  9. Hanahan D and Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70. https://doi.org/10.1016/S0092-8674(00)81683-9
  10. He L, Hannon GJ (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet, 5, 522-31. https://doi.org/10.1038/nrg1379
  11. Hu SJ, Ren G, Liu JL, et al (2008). MicroRNA expression and regulation in mouse uterus during embryo implantation. J Biol Chem, 283, 23473-84. https://doi.org/10.1074/jbc.M800406200
  12. Hwang HW, Mendell JT (2006). MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer, 94, 776-80. https://doi.org/10.1038/sj.bjc.6603023
  13. Jackman D, Pao W, Riely GJ, et al (2010). Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol, 28, 357-60. https://doi.org/10.1200/JCO.2009.24.7049
  14. Jemal A, Siegel R, Xu J, Ward E (2010). Cancer statistics, 2010. CA Cancer J Clin, 60, 277-300. https://doi.org/10.3322/caac.20073
  15. Kosaka T, Yatabe Y, Endoh H, et al (2006). Analysis of epidermal growth factor receptor gene mutation in patients with nonsmall cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res, 12, 5764-9. https://doi.org/10.1158/1078-0432.CCR-06-0714
  16. Lee KM, Choi EJ, Kim IA (2011). microRNA-7 increases radiosensitivity of human cancer cells with activated EGFRassociated signaling. Radiother Oncol, 101, 171-6. https://doi.org/10.1016/j.radonc.2011.05.050
  17. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25, 402-8. https://doi.org/10.1006/meth.2001.1262
  18. Maemondo M, Inoue A, Kobayashi K, et al (2010). Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 362, 2380-8. https://doi.org/10.1056/NEJMoa0909530
  19. Magrelli A, Azzalin G, Salvatore M, et al (2009). Altered microRNA expression patterns in hepatoblastoma patients. Transl Oncol, 2, 157-63. https://doi.org/10.1593/tlo.09124
  20. Mellinghoff IK, Cloughesy TF, Mischel PS (2007). PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res, 13, 378-81. https://doi.org/10.1158/1078-0432.CCR-06-1992
  21. Mendelsohn J, Baselga J (2000). The EGF receptor family as targets for cancer therapy. Oncogene, 19, 6550-65. https://doi.org/10.1038/sj.onc.1204082
  22. Miller TE, Ghoshal K, Ramaswamy B, et al (2008). MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem, 283, 29897-903. https://doi.org/10.1074/jbc.M804612200
  23. Mok TS, Wu YL, Thongprasert S, et al (2009). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 361, 947-57. https://doi.org/10.1056/NEJMoa0810699
  24. Pao W, Miller VA, Politi KA, et al (2005). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med, 2, e73.
  25. Pillai RS (2005). MicroRNA function: multiple mechanisms for a tiny RNA? RNA, 11, 1753-61. https://doi.org/10.1261/rna.2248605
  26. Salomon DS, Brandt R, Ciardiello F, Normanno N (1995). Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hemat, 19, 183-232. https://doi.org/10.1016/1040-8428(94)00144-I
  27. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al (2005). Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med, 353, 123-32. https://doi.org/10.1056/NEJMoa050753
  28. Sos ML, Koker M, Weir BA, et al (2009). PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res, 69, 3256-61. https://doi.org/10.1158/0008-5472.CAN-08-4055
  29. Sulis ML, Parsons R (2003). PTEN: from pathology to biology. Trends Cell Biol 13, 478-83. https://doi.org/10.1016/S0962-8924(03)00175-2
  30. Tamura M, Gu J, Matsumoto K, et al (1998). Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science, 280, 1614-7. https://doi.org/10.1126/science.280.5369.1614
  31. Thatcher N, Chang A, Parikh P, et al (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 366, 1527-37. https://doi.org/10.1016/S0140-6736(05)67625-8
  32. Weiss GJ, Bemis LT, Nakajima E, et al (2008). EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines. Ann Oncol, 19, 1053-9. https://doi.org/10.1093/annonc/mdn006
  33. Xia L, Zhang D, Du R, et al (2008). miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer, 123, 372-9. https://doi.org/10.1002/ijc.23501
  34. Yamasaki F, Johansen MJ, Zhang D, et al (2007). Acquired resistance to erlotinib in A-431 epidermoid cancer cells requires down-regulation of MMAC1/PTEN and upregulation of phosphorylated Akt. Cancer Res, 67, 5779-88. https://doi.org/10.1158/0008-5472.CAN-06-3020
  35. Yanaihara N, Caplen N, Bowman E, et al (2006). Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 9, 189-98. https://doi.org/10.1016/j.ccr.2006.01.025
  36. Yang H, Kong W, He L, et al (2008). MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res, 68, 425-33. https://doi.org/10.1158/0008-5472.CAN-07-2488
  37. Yang Z, Chen S, Luan X, et al (2009). MicroRNA-214 is aberrantly expressed in cervical cancers and inhibits the growth of HeLa cells. IUBMB Life, 61, 1075-82. https://doi.org/10.1002/iub.252
  38. Zhang XJ, Ye H, Zeng CW, et al (2010). Dysregulation of miR- 15a and miR-214 in human pancreatic cancer. J Hematol Oncol, 3, 46.
  39. Zhou C, Wu YL, Chen G, et al (2011). Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study. Lancet Oncol, 12, 735-42. https://doi.org/10.1016/S1470-2045(11)70184-X

Cited by

  1. Common Docking Domain Mutation E322K of the ERK2 Gene is Infrequent in Oral Squamous Cell Carcinomas vol.13, pp.12, 2012, https://doi.org/10.7314/APJCP.2012.13.12.6155
  2. The Role of the Dysfunctional Akt-Related Pathway in Cancer: Establishment and Maintenance of a Malignant Cell Phenotype, Resistance to Therapy, and Future Strategies for Drug Development vol.2013, pp.2090-908X, 2013, https://doi.org/10.1155/2013/317186
  3. Friend or foe: the role of microRNA in chemotherapy resistance vol.34, pp.7, 2013, https://doi.org/10.1038/aps.2013.35
  4. Chemoresistance in ovarian cancer linked to expression of microRNAs vol.88, pp.7, 2013, https://doi.org/10.3109/10520295.2013.788736
  5. MicroRNAs: short non-coding players in cancer chemoresistance vol.2, pp.1, 2014, https://doi.org/10.1186/2052-8426-2-16
  6. Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer vol.5, pp.5, 2014, https://doi.org/10.1038/cddis.2014.186
  7. Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer vol.9, pp.7, 2014, https://doi.org/10.1371/journal.pone.0103305
  8. miR-214 promotes osteosarcoma tumor growth and metastasis by decreasing the expression of PTEN vol.12, pp.4, 2015, https://doi.org/10.3892/mmr.2015.4197
  9. MiR-214 increases the sensitivity of breast cancer cells to tamoxifen and fulvestrant through inhibition of autophagy vol.14, pp.1, 2015, https://doi.org/10.1186/s12943-015-0480-4
  10. The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer vol.115, pp.11, 2016, https://doi.org/10.1038/bjc.2016.362
  11. Identification and Pharmacological Analysis of High Efficacy Small Molecule Inhibitors of EGF-EGFR Interactions in Clinical Treatment of Non-Small Cell Lung Carcinoma: a Computational Approach vol.16, pp.18, 2016, https://doi.org/10.7314/APJCP.2015.16.18.8191
  12. miR-214 inhibits invasion and migration via downregulating GALNT7 in esophageal squamous cell cancer vol.37, pp.11, 2016, https://doi.org/10.1007/s13277-016-5320-7
  13. Deregulated WWOX is involved in a negative feedback loop with microRNA-214-3p in osteosarcoma vol.38, pp.6, 2016, https://doi.org/10.3892/ijmm.2016.2800
  14. LncRNA CASC2 Interacts With miR-181a to Modulate Glioma Growth and Resistance to TMZ Through PTEN Pathway vol.118, pp.7, 2017, https://doi.org/10.1002/jcb.25910
  15. MicroRNA-targeted therapeutics for lung cancer treatment vol.12, pp.2, 2017, https://doi.org/10.1080/17460441.2017.1263298
  16. Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-00901-6
  17. Prediction Value of miR-483 and miR-214 in Prognosis and Multidrug Resistance of Esophageal Squamous Cell Carcinoma vol.17, pp.6, 2013, https://doi.org/10.1089/gtmb.2012.0518
  18. miR-214: a potential biomarker and therapeutic for different cancers vol.11, pp.2, 2015, https://doi.org/10.2217/fon.14.193
  19. miRNAs: mediators of ErbB family targeted therapy resistance vol.17, pp.10, 2016, https://doi.org/10.2217/pgs-2016-0038
  20. Inhibition of miR-23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3K/Akt pathway vol.38, pp.5, 2017, https://doi.org/10.3892/or.2017.5938
  21. Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib vol.13, pp.5, 2017, https://doi.org/10.3892/ol.2017.5829
  22. Concise Review: Resistance to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: The Role of Cancer Stem Cells vol.36, pp.5, 2018, https://doi.org/10.1002/stem.2787
  23. MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours vol.13, pp.4, 2018, https://doi.org/10.1007/s11523-018-0580-3