Wang Yitao, Qin Xian, Guo Tao, Liu Pengpeng, Wu Ping, Liu Zhisu
Department of General Surgery, Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
J Exp Clin Cancer Res. 2017 Jul 17;36(1):97. doi: 10.1186/s13046-017-0569-2.
Hepatocellular carcinoma (HCC) remains difficult to cure due to lack of effective treatment and the molecular mechanisms are complex and not completely understood. In this study, We investigated the role of CDK16 in tumor progression of HCC.
We interrogated the expression level of CDK16 by polymerase chain reaction and immunohistochemistry(IHC) and studied its clinical significance. The functional role of CDK16 on HCC was studied via gain and loss of function in vitro and in vivo. Luciferase reporter assay and Chromatin immunoprecipitation(ChIP) assay were performed to investigate the transcriptional and post-transcriptional mechanisms involved in the regulation of CDK16.
CDK16 expression was significantly up-regulated in HCC and higher expression of CDK16 was positively correlated with aggressive clinicopathological phenotype and poorer survival rates. Functionally, knockdown of CDK16 suppressed proliferation in vitro and in vivo. Inactivation of CDK16 also induced apoptosis and cell cycle arrest. Most importantly, CDK16 promoted epithelial mesenchymal transition and tumor invasion by activating β-catenin signaling. In addition, We identified E2F1 as a positive transcriptional regulator of CDK16. Moreover, down regulation of miR-125b-5p enhanced CDK16 expression at post-transcriptional level.
We provided the first evidence that CDK16 is an bona fide oncogene in HCC, and multiple activating mechanisms at transcriptional and posttranscriptional levels together contributes to CDK16 up-regulation in HCC.
由于缺乏有效的治疗方法，肝细胞癌（HCC）仍然难以治愈，其分子机制复杂，尚未完全明确。在本研究中，我们调查了细胞周期蛋白依赖性激酶16（CDK16）在HCC肿瘤进展中的作用。
我们通过聚合酶链反应和免疫组织化学（IHC）检测CDK16的表达水平，并研究其临床意义。通过体外和体内功能获得和功能缺失研究CDK16对HCC的功能作用。进行荧光素酶报告基因检测和染色质免疫沉淀（ChIP）检测，以研究参与CDK16调控的转录和转录后机制。
CDK16在HCC中表达显著上调，CDK16的高表达与侵袭性临床病理表型和较差的生存率呈正相关。在功能上，敲低CDK16抑制体外和体内增殖。CDK16失活还诱导细胞凋亡和细胞周期停滞。最重要的是，CDK16通过激活β-连环蛋白信号促进上皮间质转化和肿瘤侵袭。此外，我们确定E2F1是CDK16的正向转录调节因子。此外，miR-125b-5p的下调在转录后水平增强了CDK16的表达。
我们提供了首个证据，证明CDK16是HCC中的一个真正癌基因，转录和转录后水平的多种激活机制共同导致HCC中CDK16上调。
