MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines
MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines
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DOI：
10.7314/apjcp.2012.13.1.255
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发表时间：
2012-01-01
影响因子：
--
通讯作者：
Zhou, Cai-Cun
中科院分区：
文献类型：
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作者：
Wang, Yong-Sheng;Wang, Yin-Hua;Zhou, Cai-Cun
具有活化表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者从EGFR-酪氨酸激酶抑制剂（EGFR- tkis）治疗中获得临床益处，即吉非替尼和厄洛替尼。然而，这些患者最终会对EGFR-TKIs产生耐药性。尽管这种获得性耐药可能是EGFR基因继发性突变的结果，如T790M或MET原癌基因扩增，但还有其他机制需要探索。MicroRNAs （miRs）是一类小的非编码rna，在肿瘤发生、肿瘤进展和化疗耐药中起着关键作用。在本研究中，我们首先通过将正常的HCC827细胞（一种框架内EGFR基因缺失746E-750A的NSCLC细胞系）暴露于增加浓度的吉非替尼中，成功建立了吉非替尼耐药细胞系HCC827/GR。然后，我们发现miR-214在HCC827/GR中显著上调。我们还发现miR-214和PTEN在HCC827/GR中呈负表达。miR-214的下调改变了PTEN和p-AKT的表达，使HCC827/GR对吉非替尼重新敏感。综上所述，miR-214可能通过PTEN/AKT信号通路调控HCC827对吉非替尼的获得性耐药。因此，抑制miR-214可能逆转对EGFR-TKIs治疗的获得性耐药。
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.