Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
IUBMB Life. 2019 Mar;71(3):347-356. doi: 10.1002/iub.1983. Epub 2018 Dec 11.
Aberrant activation of cyclin-dependent kinase 9 (CDK9) is widespread in human cancers. However, the underlying mechanisms of CDK9 activation and the therapeutic potential of CDK9 inhibition in cervical cancer remain largely unknown. Here, we report that CDK9 is gradually upregulated during cervical lesion progression and regulated by HPV16 E6. CDK9 levels are highly correlated with FIGO stage, pathological grade, deep-stromal invasion, tumor size, and lymph nodes metastasis. Knockdown of CDK9 by specific siRNA inhibits cervical cancer cell proliferation in vitro, as well as tumorigenesis in vivo. CDK9 inhibition causes a significant decreased AKT2 and increased p53 protein expression revealing novel CDK9-regulatory mechanisms. Overexpression of AKT2 rescued the suppressive effects caused by CDK9 knockdown, suggesting that AKT2 induction is essential for CDK9-induced transformation. Moreover, CDK9 expression was positively correlated with AKT2 and negatively correlated with p53 in cervical cancer tissues with HPV16 infection. Our findings demonstrate for the first time that CDK9 acts as a proto-oncogene in cervical cancer, modulating cell proliferation and apoptosis through AKT2/p53 pathway. Therefore, our data provide novel mechanistic insights into the role of CDK9 in cervical cancer development. © 2018 IUBMB Life, 71(3):347-356, 2019.
细胞周期蛋白依赖性激酶 9（CDK9）的异常激活广泛存在于人类癌症中。然而，CDK9 的激活机制以及在宫颈癌中抑制 CDK9 的治疗潜力在很大程度上仍然未知。在这里，我们报告 CDK9 在宫颈病变进展过程中逐渐上调，并受 HPV16 E6 调控。CDK9 水平与 FIGO 分期、病理分级、深肌层浸润、肿瘤大小和淋巴结转移高度相关。特异性 siRNA 敲低 CDK9 可抑制体外宫颈癌细胞增殖以及体内肿瘤发生。CDK9 抑制导致 AKT2 蛋白表达显著降低和 p53 蛋白表达增加，揭示了新的 CDK9 调控机制。AKT2 的过表达挽救了 CDK9 敲低引起的抑制作用，表明 AKT2 的诱导对于 CDK9 诱导的转化是必需的。此外，在 HPV16 感染的宫颈癌组织中，CDK9 的表达与 AKT2 呈正相关，与 p53 呈负相关。我们的研究结果首次表明，CDK9 作为宫颈癌中的原癌基因，通过 AKT2/p53 通路调节细胞增殖和凋亡。因此，我们的数据为 CDK9 在宫颈癌发生发展中的作用提供了新的机制见解。
