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


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.


  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.
  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.
  4. Burris HA, 3rd (2009). Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs. Oncogene, 28 Suppl 1, S4-13.
  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.
  8. Farazi TA, Spitzer JI, Morozov P, et al (2011). miRNAs in human cancer. J Pathol, 223, 102-15.
  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.
  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.
  12. Kong YW, Ferland-McCollough D, Jackson TJ, et al (2012). microRNAs in cancer management. Lancet Oncol, 13, e249-58.
  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.
  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.
  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.
  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.
  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.
  18. Mujahid S, Nielsen HC, Volpe MV (2013). MiR-221 and miR-130a regulate lung airway and vascular development. PLoS One, 8, e55911.
  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.
  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.
  22. Ramachandran PV, Ignacimuthu S (2012). RNA Interference as a Plausible Anticancer Therapeutic Tool. Asian Pac J Cancer P, 13, 2445-52.
  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.
  24. Sekido Y (2010). Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci, 101, 1-6.
  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.
  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.
  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.
  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.
  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.

Cited by

  1. Regulatory Mechanisms of Annexin-Induced Chemotherapy Resistance in Cisplatin Resistant Lung Adenocarcinoma vol.15, pp.7, 2014,
  2. MicroRNA-130a is down-regulated in hepatocellular carcinoma and associates with poor prognosis vol.31, pp.10, 2014,
  3. The molecular mechanism of HOTAIR in tumorigenesis, metastasis, and drug resistance vol.46, pp.12, 2014,
  4. Combinational treatment with microRNA-133b and cetuximab has increased inhibitory effects on the growth and invasion of colorectal cancer cells by regulating EGFR vol.12, pp.4, 2015,
  5. Non-small-cell lung cancer and miRNAs: novel biomarkers and promising tools for treatment vol.128, pp.10, 2015,
  6. Clinical Efficacy and Possible Applications of Genomics in Lung Cancer vol.16, pp.5, 2015,
  7. Targeting the MET pathway for potential treatment of NSCLC vol.19, pp.5, 2015,
  8. Long Non-coding RNAs and Drug Resistance vol.16, pp.18, 2016,
  9. MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells vol.35, pp.1, 2016,
  10. MiR-130b inhibits proliferation and induces apoptosis of gastric cancer cells via CYLD vol.37, pp.6, 2016,
  11. Chicken gga-miR-130a targets HOXA3 and MDFIC and inhibits Marek’s disease lymphoma cell proliferation and migration vol.43, pp.7, 2016,
  12. STAT1 Inhibits MiR-181a Expression to Suppress Colorectal Cancer Cell Proliferation Through PTEN/Akt vol.118, pp.10, 2017,
  13. LncRNA CCAT1/miR-130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4 vol.18, pp.12, 2017,
  14. The role of miR-130a in cancer vol.24, pp.4, 2017,
  15. MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact vol.39, pp.7, 2017,
  16. Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients vol.11, pp.1, 2015,
  17. MicroRNA-130a inhibits growth and metastasis of osteosarcoma cells by directly targeting ZEB1 vol.16, pp.3, 2017,
  18. Complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma vol.8, pp.1, 2018,
  19. miR-1-3p and miR-206 sensitizes HGF-induced gefitinib-resistant human lung cancer cells through inhibition of c-Met signalling and EMT vol.22, pp.7, 2018,
  20. miR-130a-3p regulated TGF-β1-induced epithelial-mesenchymal transition depends on SMAD4 in EC-1 cells pp.20457634, 2019,