| 王聪慧,张可人,马春爽,朱 亮,雷绘敏.ALDH1A1诱导肺腺癌细胞发生上皮-间质转化及化疗耐药[J].,2018,(24):4601-4606 |
| ALDH1A1诱导肺腺癌细胞发生上皮-间质转化及化疗耐药 |
| ALDH1A1 Induces the Epithelial-mesenchymal Transition and Drug Resistance in LAC |
| 投稿时间：2018-09-05 修订日期：2018-09-30 |
| DOI：10.13241/j.cnki.pmb.2018.24.001 |
| 中文关键词: 耐药 肿瘤干细胞 上皮-间质转化 醛脱氢酶1A1 双硫仑 |
| 英文关键词: Drug resistance CSC EMT ALDH1A1 DSF |
| 基金项目:国家自然科学基金项目(81573018，81872822) |
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| 中文摘要: |
| 摘要 目的：探索醛脱氢酶1A1(aldehyde dehydrogenase 1A1，ALDH1A1)在肺腺癌细胞(lung adenocarcinoma cell，LAC)化疗耐药中的作用及机制，为肺癌临床治疗和新型药物的研发提供实验依据。方法：采用慢病毒载体构建ALDH1A1高表达肺腺癌细胞模型，并通过流式细胞术和western blot技术对该细胞模型进行验证。通过CCK8法检测ALDH1A1高表达肺腺癌细胞对肺癌治疗药物顺铂(cisplatin，DDP)、紫杉醇(paclitaxcel)、厄洛替尼(erlotinib)和吉非替尼(gefitinib)的耐药性。通过检测肿瘤干细胞(cancer stem cell，CSC)分子标志物、上皮-间质转化(Epithelial-Mesenchymal Transition，EMT)分子标志物及细胞迁移能力探讨ALDH1A1高表达对肺腺癌细胞的干性和EMT特征的影响。双硫仑(disulfiram，DSF)是ALDH的抑制剂，我们通过CCK8法和transwell细胞迁移实验探究DSF对肺腺癌细胞体外生长和迁移能力的影响，体内实验探究DSF和厄洛替尼联合用药对HCC827-ALDH1A1细胞皮下异种移植瘤生长的影响。结果：ALDH1A1高表达诱导肺腺癌细胞对厄洛替尼、吉非替尼、紫杉醇和顺铂产生不同程度的耐药，干细胞标志物CD44、CD133蛋白表达上调，EMT间充质标志物vimentin蛋白表达上调，transwell实验结果显示ALDH1A1高表达肺腺癌细胞的迁移能力增强，使用ALDH靶向抑制剂DSF能选择性抑制ALDH1A1高表达肺腺癌细胞所增高的迁移能力并克服HCC827-ALDH1A1细胞皮下异种移植瘤的生长，延缓体内耐药。结论：ALDH1A1能诱导肺腺癌细胞对多种抗肺癌药物产生耐药并发生干细胞样转化，靶向抑制ALDH酶活性可克服由ALDH1A1高表达所产生的耐药，为肺癌的临床治疗提供新的思路。 |
| 英文摘要: |
| ABSTRACT Objective: To explore the role and mechanism of ALDH1A1 in the chemotherapy resistance of lung adenocarcinoma cells, and provide experimental basis for clinical treatment of lung cancer and development of new drugs. Methods: Lentivirus was used to establish a lung adenocarcinoma cell model with ALDH1A1 overexpression, which was verified by flow cytometry and western blot. CCK8 was then used to detect the resistance of ALDH1A1 overexpressed lung adenocarcinoma cells to common anti-lung cancer drugs such as cisplatin (DDP), paclitaxel, erlotinib and gefitinib. The effect of ALDH1A1 overexpression on the stemness and EMT characteris- tics of lung adenocarcinoma cells were investigated by detecting the CSC and EMT markers and cell migration. Disulfiram (DSF) is an inhibitor of ALDH. We investigated the effects of DSF on the growth and migration of LACs in vitro by CCK8 cell viability assay and transwell migration assay. Inhibitory effect of DSF combined with erlotinib was detected on the subcutaneous xenografts of HCC827-ALDH1A1 cells in vivo. Results: Overexpression of ALDH1A1 induced different degrees of resistance in lung adenocarcinoma cells to erlotinib, gefitinib, paclitaxel and cisplatin. Stem cell markers CD44, CD133 and EMT mesenchymal marker vimentin were up- regulated. Transwell results showed that the migration of lung adenocarcinoma cells with ALDH1A1 overexpression was enhanced. DSF, a targeting inhibitor of ALDH, selectively inhibits the increased migration of lung adenocarcinoma cells overexpressing ALDH1A1, over- comes the growth of subcutaneous xenografts of HCC827-ALDH1A1 cells and delays drug resistance in vivo. Conclusion: ALDH1A1 can induce lung adenocarcinoma cells to develop resistance to various anti-lung cancer drugs and endue cells with stemness. Targeted in- hibition of ALDH enzyme activity can overcome the drug resistance caused by the overexpression of ALDH1A1, providing a new idea for clinical treatment of lung cancer. |
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