FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop.
FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop.
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FOXM1 通过 MET/AKT 依赖的正反馈环赋予肺腺癌吉非替尼耐药性
DOI：
10.18632/oncotarget.11043
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Wen N
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang W;Wen L;Yang H;Wen M;Yun Y;Zhao L;Zhu X;Tian L;Luo E;Li Y;Liu W;Wen N
吉非替尼耐药仍然是肺腺癌治疗中的主要问题。然而，吉非替尼耐药的分子机制尚不完全清楚。在这项研究中，我们研究了转录因子Forkhead box蛋白M1(FOXM1)在肺腺癌细胞对吉非替尼耐药中的关键作用。体外药敏实验表明，FOXM1抑制PC9/GR和HCC827/GR细胞对吉非替尼的敏感性，而FOXM1过表达则增加PC9和HCC827细胞对吉非替尼的耐药性。FOXM1的增加导致肝细胞生长因子受体(MET)的上调，从而导致蛋白激酶B(AKT)途径的激活，而FOXM1的下调则相反。FOXM1直接与MET启动子区域结合，在转录水平上调控MET的启动子活性和表达。MET/AKT通路上调肺腺癌细胞FOXM1的表达。用LY294002抑制PAKT或用PHA-665752抑制pMET可显著抑制肺腺癌细胞FOXM1的表达。重要的是，我们进一步证明FOXM1、PAKT和MET在肺腺癌组织中的表达水平显著高于正常肺组织，并且这三种生物标志物在肺腺癌组织中同时过表达。综上所述，我们的结果表明FOXM1促进肺腺癌细胞对吉非替尼的获得性耐药，并且FOXM1与MET/AKT信号串扰形成正反馈环路促进肺腺癌的发展。
Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development.