Cyclin-dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway
Cyclin-dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway
复制标题
细胞周期蛋白依赖性激酶 9 通过 AKT2/p53 通路促进宫颈癌发展
DOI：
10.1002/iub.1983
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发表时间：
2019-03-01
期刊：
影响因子：
4.6
通讯作者：
Lu, Weiguo
中科院分区：
文献类型：
--
作者：
Xu, Junfen;Xu, Shanshan;Lu, Weiguo
细胞周期蛋白依赖性激酶9（CDK 9）的异常激活在人类癌症中广泛存在。然而，CDK 9活化的潜在机制和CDK 9抑制在宫颈癌中的治疗潜力在很大程度上仍然未知。在这里，我们报告说，CDK 9在宫颈病变进展过程中逐渐上调，并受HPV 16 E6的调节。CDK 9水平与FIGO分期、病理分级、深间质浸润、肿瘤大小和淋巴结转移高度相关。通过特异性siRNA敲低CDK 9抑制体外宫颈癌细胞增殖以及体内肿瘤发生。CDK 9抑制导致AKT 2显著降低和p53蛋白表达增加，揭示了新的CDK 9调节机制。AKT 2的过表达挽救了由CDK 9敲低引起的抑制作用，表明AKT 2诱导对于CDK 9诱导的转化是必需的。在HPV 16感染的宫颈癌组织中，CDK 9与AKT 2的表达呈正相关，与p53的表达呈负相关。我们的研究结果首次证明CDK 9在宫颈癌中作为原癌基因，通过AKT 2/p53途径调节细胞增殖和凋亡。因此，我们的数据为CDK 9在宫颈癌发展中的作用提供了新的机制见解。(c)2018 IUBMB Life，71（3）：347-356，2019
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. (c) 2018 IUBMB Life, 71(3):347-356, 2019