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MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

  • Zhou, Yong-Ming (Department of Geriatrics, Wuhan University, Renmin Hospital) ;
  • Liu, Juan (Department of Geriatrics, Wuhan University, Renmin Hospital) ;
  • Sun, Wei (Department of Thoracic Surgery, Tongji Hospital of Huazhong University of Science and Technology)
  • Published : 2014.02.01

Abstract

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is used for its treatment; however, drug resistance is a major obstacle. Expression of Met has been associated with both primary and acquired resistance to gefitinib, but the mechanisms regulating its expression are not fully understood. Recently, miRNAs such as miR-130a have been shown to play a role in gefitinib resistance, but importance in NSCLC and relationships with Met have not been fully explored. Here we show that miR-130a is over-expressed in gefitinibsensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Moreover, miR-130a expression was negatively correlated with that of Met. Further analysis revealed that over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines, suggesting that miR-130a overcomes gefitinib resistance. We also demonstrated that miR-130a binds to the 3'-UTR of Met and significantly suppresses its expression. Finally, our results showed that over-expressing Met could "rescue" the functions of miR-130a regarding cell apoptosis and proliferation after cells are treated with gefitinib. These findings indicate that the miR-130a/Met axis plays an important role in gefitinib resistance in NSCLC. Thus, the miR-130a/Met axis may be an effective therapeutic target in gefitinib-resistant lung cancer patients.

References

  1. Acunzo M, Visone R, Romano G, et al (2012). miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene, 31, 634-42.
  2. Belalcazar A, Azana D, Perez CA, et al (2012). Targeting the Met pathway in lung cancer. Expert Rev Anticancer Ther, 12, 519-28. https://doi.org/10.1586/era.12.16
  3. Boll K, Reiche K, Kasack K, et al (2013). MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene, 32, 277-85. https://doi.org/10.1038/onc.2012.55
  4. Burris HA, 3rd (2009). Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs. Oncogene, 28 Suppl 1, S4-13. https://doi.org/10.1038/onc.2009.196
  5. Chen Y, Gorski DH (2008). Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood, 111, 1217-26.
  6. Dimitroulis J, Stathopoulos GP (2005). Evolution of non-small cell lung cancer chemotherapy (Review). Oncol Rep, 13, 923-30.
  7. 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
  8. Farazi TA, Spitzer JI, Morozov P, et al (2011). miRNAs in human cancer. J Pathol, 223, 102-15. https://doi.org/10.1002/path.2806
  9. Garofalo M, Romano G, Di Leva G, et al (2012). EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med, 18, 74-82.
  10. Gazdar AF (2009). Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 28 Suppl 1, S24-31. https://doi.org/10.1038/onc.2009.198
  11. Guo A, Villen J, Kornhauser J, et al (2008). Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A, 105, 692-7. https://doi.org/10.1073/pnas.0707270105
  12. Kong YW, Ferland-McCollough D, Jackson TJ, et al (2012). microRNAs in cancer management. Lancet Oncol, 13, e249-58. https://doi.org/10.1016/S1470-2045(12)70073-6
  13. Kosaka T, Yatabe Y, Endoh H, et al (2006). Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res, 12, 5764-9. https://doi.org/10.1158/1078-0432.CCR-06-0714
  14. Li H, Schmid-Bindert G, Wang D, et al (2011). Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome gefitinib-resistance in non-small cell lung cancer cell lines. Adv Med Sci, 56, 275-84. https://doi.org/10.2478/v10039-011-0043-x
  15. Luo W, Huang B, Li Z, et al (2013). MicroRNA-449a is downregulated in non-small cell lung cancer and inhibits migration and invasion by targeting c-Met. PLoS One, 8, e64759. https://doi.org/10.1371/journal.pone.0064759
  16. Matoulkova E, Michalova E, Vojtesek B, et al (2012). The role of the 3' untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA Biol, 9, 563-76. https://doi.org/10.4161/rna.20231
  17. Molina JR, Yang P, Cassivi SD, et al (2008). Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc, 83, 584-94. https://doi.org/10.1016/S0025-6196(11)60735-0
  18. Mujahid S, Nielsen HC, Volpe MV (2013). MiR-221 and miR-130a regulate lung airway and vascular development. PLoS One, 8, e55911. https://doi.org/10.1371/journal.pone.0055911
  19. Oxnard GR, Miller VA (2010). Use of erlotinib or gefitinib as initial therapy in advanced NSCLC. Oncology (Williston Park), 24, 392-9.
  20. Paez JG, Janne PA, Lee JC, et al (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science, 304, 1497-1500. https://doi.org/10.1126/science.1099314
  21. 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. https://doi.org/10.1371/journal.pmed.0020073
  22. Ramachandran PV, Ignacimuthu S (2012). RNA Interference as a Plausible Anticancer Therapeutic Tool. Asian Pac J Cancer P, 13, 2445-52. https://doi.org/10.7314/APJCP.2012.13.6.2445
  23. Sandberg R, Neilson JR, Sarma A, et al (2008). Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer microRNA target sites. Science, 320, 1643-7. https://doi.org/10.1126/science.1155390
  24. Sekido Y (2010). Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci, 101, 1-6. https://doi.org/10.1111/j.1349-7006.2009.01336.x
  25. Sequist LV, Martins RG, Spigel D, et al (2008). First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol, 26, 2442-9. https://doi.org/10.1200/JCO.2007.14.8494
  26. Suda K, Murakami I, Katayama T, et al (2010). Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clin Cancer Res, 16, 5489-98. https://doi.org/10.1158/1078-0432.CCR-10-1371
  27. Xu N, Shen C, Luo Y, et al (2012). Upregulated miR-130a increases drug resistance by regulating RUNX3 and Wnt signaling in cisplatin-treated HCC cell. Biochem Biophys Res Commun, 425, 468-72. https://doi.org/10.1016/j.bbrc.2012.07.127
  28. Yang F, Miao L, Mei Y, et al (2013). Retinoic acid-induced HOXA5 expression is co-regulated by HuR and miR-130a. Cell Signal, 25, 1476-85. https://doi.org/10.1016/j.cellsig.2013.03.015
  29. Yang L, Li N, Wang H, et al (2012). Altered microRNA expression in cisplatin-resistant ovarian cancer cells and upregulation of miR-130a associated with MDR1/P-glycoprotein-mediated drug resistance. Oncol Rep, 28, 592-600.
  30. Zhang W, Mendoza MC, Pei X, et al (2012). Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase (ERK) signaling. J Biol Chem, 287, 11850-8. https://doi.org/10.1074/jbc.M111.258236

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