Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway

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• 作者：Huanxin Liu (1) (2)
  Jie Huang (1)
  Juan Peng (1) (3)
  Xiaoxia Wu (2)
  Yan Zhang (2)
  Weiliang Zhu (4)
  Linlang Guo (1)
  
  1. Department of Pathology ; Zhujiang Hospital ; Southern Medical University ; Guangzhou ; China
  2. Department of Pathology ; Guangdong Provincial Corps Hospital of Chinese People鈥檚 Armed Police Forces ; Guangzhou Medical College ; Guangzhou ; China
  3. Department of Pathology ; the Third Affiliated Hospital of Guangzhou Medical University ; Guangzhou ; China
  4. Department of Oncology ; Zhujiang Hospital ; Southern Medical University ; Guangzhou ; China
  
• 关键词：SCLC ; KCNJ2/Kir2.1 ; Chemoresistance ; MRP1/ABCC1 ; miR ; 7 ; Ras/MAPK pathway
• 刊名：Molecular Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：14
• 期：1
• 全文大小：3,626 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background KCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel family, is commonly expressed in a wide range of tissues and cell types. Previous studies indicated that Kir2.1 may be associated with SCLC multidrug resistance (MDR). However, whether Kir2.1 can regulate MDR and its underlying mechanisms remain poorly understood in SCLC. Methods KCNJ2/Kir2.1 expression was examined in tissues from fifty-two SCLC cases by immunohistochemistry. Overexpression or knockdown of KCNJ2/Kir21 was performed in multidrug-resistant SCLC cell lines (H69AR and H446AR) and their parental cell lines (H69 and H446) to assess its influence on cell growth, apoptosis, the cell cycle and chemoresistance. Results KCNJ2/Kir2.1 was expressed in 44.23% (23/52) of SCLC tissues. Overexpression of KCNJ2/Kir2.1 was correlated with the clinical stage and chemotherapy response in SCLC patients. Knockdown of KCNJ2/Kir2.1 expression using KCNJ2/Kir2.1 shRNA in H69AR and H446AR cells inhibited cell growth and sensitized the cancer cells to chemotherapeutic drugs by increasing cell apoptosis and cell cycle arrest. Forced KCNJ2/Kir2.1 expression in H69 and H446 cells promoted cell growth and enhanced multidrug resistance via reduced drug-induced apoptosis accompanied by cell cycle arrest. KCNJ2/Kir2.1 expression was also influenced by PKC and MEK inhibitors. In addition, multidrug resistance protein 1 (MRP1/ABCC1) was confirmed to interact with KCNJ2/Kir2.1 by Co-IP assays. Conclusions KCNJ2/Kir2.1 modulates cell growth and drug resistance by regulating MRP1/ABCC1 expression and is simultaneously regulated by the Ras/MAPK pathway and miR-7. KCNJ2/Kir2.1 may be a prognostic predictor and a potentially novel target for interfering with chemoresistance in SCLC.