Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital/the First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410005, People's Republic of China; Key Laboratory of Protein Chemistry, Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China; Laboratory of Hepatobiliary Molecular Oncology, Hunan Provincial People's Hospital, Changsha, Hunan 410005, People's Republic of China.
Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital/the First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410005, People's Republic of China.
Gene. 2018 Oct 5;673:46-55. doi: 10.1016/j.gene.2018.06.047. Epub 2018 Jun 18.
Previous studies have shown that high levels of PLK1 are expressed in HCC, and PLK1 inhibitors are being tested in clinical trials. However, the mechanisms, which regulate PLK1 expression in HCC, have not been clarified. Here, we show that induction of let-7b over-expression inhibits the PLK1-regulated luciferase activity in HEK-293T cells, and decreases the levels of PLK1 expression in HCC cells. Furthermore, the levels of let-7b expression were negatively correlated with PLK1 expression in HCC tissues. Let-7b over-expression inhibited the proliferation of HCC cells and promoted their apoptosis, which were partially rescued by increased PLK1 expression. Let-7b over-expression decreased the levels of PLK1, CDC25C and Survivin phosphorylation and CDC2, β-catenin, TCF-4 expression, which were mitigated by increased PLK1 expression in MHCC-97H cells. Let-7b over-expression inhibited the development and growth of implanted HCC tumors in mice by decreasing PLK1 and Survivin expression in the tumors. Together, our data indicated that let-7b targeted PLK1 to inhibit HCC growth and induce their apoptosis by attenuating the PLK1-mediated Survivin phosphorylation. Our findings may provide new insights into the pathogenesis of HCC.
先前的研究表明，PLK1 在 HCC 中表达水平较高，PLK1 抑制剂正在临床试验中进行测试。然而，调节 HCC 中 PLK1 表达的机制尚未阐明。在这里，我们表明诱导 let-7b 过表达可抑制 HEK-293T 细胞中 PLK1 调节的荧光素酶活性，并降低 HCC 细胞中 PLK1 的表达水平。此外，let-7b 的表达水平与 HCC 组织中 PLK1 的表达水平呈负相关。let-7b 过表达抑制 HCC 细胞的增殖并促进其凋亡，而增加 PLK1 的表达可部分挽救这种作用。let-7b 过表达降低了 PLK1、CDC25C 和 Survivin 磷酸化以及 CDC2、β-catenin、TCF-4 的表达水平，而在 MHCC-97H 细胞中增加 PLK1 的表达可减轻这种作用。let-7b 过表达通过降低肿瘤中的 PLK1 和 Survivin 表达，抑制了小鼠植入 HCC 肿瘤的发展和生长。总之，我们的数据表明，let-7b 通过减弱 PLK1 介导的 Survivin 磷酸化来靶向 PLK1 以抑制 HCC 生长并诱导其凋亡。我们的发现可能为 HCC 的发病机制提供新的见解。
