Jin Dong Hao, Kim Yujin, Lee Bo Bin, Han Joungho, Kim Hong Kwan, Shim Young Mog, Kim Duk-Hwan
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746, Korea.
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Korea.
Oncotarget. 2017 Oct 6;8(60):101509-101519. doi: 10.18632/oncotarget.21552. eCollection 2017 Nov 24.
A target molecule responsible for cell cycle arrest by metformin was discovered using a gene chip array in lung cancer cells and the effect of metformin on E2F8 was assessed. The siRNA-mediated knockdown of E2F8 significantly suppressed G1-S progression while ectopic expression of E2F8 relieved metformin-induced G1 arrest. The mRNA levels of p21 were found to be inversely related to those of E2F8 in lung cancer cells while siRNA-mediated knockdown of p21 partly rescued siE2F8-induced arrest of the cell cycle. Metformin had no effect on degradation of E2F8 mRNA. Activation and inhibition of AMPK by AICAR and Dorsomorphin, respectively, did not affect E2F8 suppression by metformin. The clinical significance of E2F8 was analyzed in The Cancer Genome Atlas (TCGA) data. One hundred six (13%) of 848 TCGA lung cancers overexpressed E2F8 mRNA. The overexpression of E2F8 was associated with poor overall survival (adjusted hazard ratio = 1.58, 95% confidence interval = 1.13-2.22; P = 0.008). The present study suggests that metformin may induce cell cycle arrest at the G1 phase by suppressing E2F8 expression in lung cancer cells. In addition, E2F8 may be associated with poor overall survival in lung cancer patients irrespective of histology.
利用基因芯片阵列在肺癌细胞中发现了一种由二甲双胍导致细胞周期停滞的靶分子，并评估了二甲双胍对E2F8的作用。E2F8的siRNA介导敲低显著抑制了G1-S期进程，而E2F8的异位表达缓解了二甲双胍诱导的G1期停滞。在肺癌细胞中发现p21的mRNA水平与E2F8的mRNA水平呈负相关，而p21的siRNA介导敲低部分挽救了siE2F8诱导的细胞周期停滞。二甲双胍对E2F8 mRNA的降解没有影响。分别用AICAR和 Dorsomorphin激活和抑制AMPK，并不影响二甲双胍对E2F8的抑制作用。在癌症基因组图谱（TCGA）数据中分析了E2F8的临床意义。848例TCGA肺癌中有106例（13%）E2F8 mRNA过表达。E2F8的过表达与总生存期较差相关（校正风险比=1.58，95%置信区间=1.13-2.22；P=0.008）。本研究表明，二甲双胍可能通过抑制肺癌细胞中E2F8的表达诱导细胞周期在G1期停滞。此外，无论组织学类型如何，E2F8可能与肺癌患者较差的总生存期相关。
