Lu Longfeng, Han Han, Tian Yuan, Li Wenjuan, Zhang Jinxiang, Feng Maohui, Li Youjun
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
Department of Surgery, Wuhan Union Hospital, Wuhan, China.
Mol Carcinog. 2015 Nov;54(11):1467-79. doi: 10.1002/mc.22223. Epub 2014 Oct 4.
Dysregulation of c-Myc (Myc) has been shown to contribute to progression of hepatocellular carcinoma, however, the detailed molecular mechanism remains poorly understood. Here, we report that Myc binds to the Aurora kinase A (Aurka) promoter and induces expression of Aurka in HCC cells. Increased expression of Aurka correlates with that of Myc in HCC. Nuclear accumulation of Aurka was confirmed by subcellular protein fractionation and immunoblot experiments in HCC cells. Myc inhibition decreases the nuclear accumulation of Aurka in HCC cells. Also Aurka accumulating in the nucleus up-regulates Myc transcription by binding the Myc promoter containing the highly conserved CCCTCCCCA in the NHE region of the CpG islands. Inhibition of Myc or Aurka diminishes the malignant phenotypes of HCC cells by down-regulating some common target genes. Also Aurka and Myc mediates the effects of each other, at least partially, on proliferation, anchorage-independent soft agar growth, and ATP production. Blocking Aurka in an orthotopic model significantly impairs tumor growth in mice. These results identify a Myc-Aurka feedback loop in which Myc and Aurka regulate expression of each other at the transcriptional level and both play an important role in hepatocarcinogenesis.
c-Myc（Myc）失调已被证明与肝细胞癌进展有关，然而，详细的分子机制仍知之甚少。在此，我们报告Myc与极光激酶A（Aurka）启动子结合并诱导肝癌细胞中Aurka的表达。Aurka表达增加与肝癌中Myc的表达相关。通过亚细胞蛋白质分级分离和免疫印迹实验在肝癌细胞中证实了Aurka的核积累。Myc抑制降低了肝癌细胞中Aurka的核积累。同样，在细胞核中积累的Aurka通过结合CpG岛NHE区域中含有高度保守的CCCTCCCCA的Myc启动子来上调Myc转录。抑制Myc或Aurka通过下调一些共同的靶基因来减少肝癌细胞的恶性表型。此外，Aurka和Myc至少部分地相互介导对增殖、非锚定依赖的软琼脂生长和ATP产生的影响。在原位模型中阻断Aurka可显著损害小鼠肿瘤生长。这些结果确定了一个Myc-Aurka反馈环，其中Myc和Aurka在转录水平上相互调节表达，并且两者在肝癌发生中都起重要作用。
