MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer.
MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer.
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人乳头瘤病毒16 E7上调的MicroRNA-27b通过靶向polo样激酶2促进宫颈癌增殖并抑制细胞凋亡
DOI：
10.18632/oncotarget.7531
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发表时间：
2016-04-12
期刊：
影响因子：
--
通讯作者：
Wang Q
中科院分区：
文献类型：
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作者：
Liu F;Zhang S;Zhao Z;Mao X;Huang J;Wu Z;Zheng L;Wang Q
高危型人乳头瘤病毒感染与宫颈癌有关，然而，HPV癌基因调控的miRNA在癌症进展中的作用在很大程度上仍然未知。在此，我们敲低HPV 16阳性CaSki细胞系中的内源性E6/E7，使用miRNA阵列筛选与对照相比miRNA表达谱的差异。在E6/E7沉默的CaSki细胞中，38个miRNAs表达下调，6个miRNAs表达上调（变化>2倍，P <0.05）。在E6/E7沉默的CaSki和SiHa细胞中通过qPCR验证miR-27 b、miR-20 a、miR-24、miR-93和miR-106 b的水平。miR-27 b在E7的上调作用下，促进CaSki和SiHa细胞的增殖和侵袭，抑制紫杉醇诱导的细胞凋亡。双荧光素酶实验证实miR-27 b通过“种子区”下调其靶基因PLK 2。肿瘤抑制剂PLK 2抑制SiHa细胞增殖，降低细胞活力，并促进紫杉醇/顺铂诱导的细胞凋亡。此外，发现DGCR 8介导HPV 16 E7对miR-27 b的上调。我们的研究表明，HPV 16 E7可通过增加DGCR 8促进miR-27 b的生成，从而通过下调PLK 2促进细胞增殖，抑制紫杉醇诱导的细胞凋亡。这些发现为深入了解病毒癌基因、miR-27 b和PLK 2之间的相互作用网络提供了新的思路，也为今后利用miR-27 b反义核酸治疗宫颈癌提供了新的思路。
The infection with high-risk human papillomavirus is linked to cervical cancer, nevertheless, the role of miRNAs regulated by HPV oncogenes in cancer progression remain largely unknown. Here, we knocked down endogenous E6/E7 in HPV16-positive CaSki cell lines, screened differences in miRNA expression profile with control using miRNA array. 38 miRNAs were down-regulated and 6 miRNAs were up-regulated in the E6/E7 silenced CaSki cells (>2-fold changes with P <0.05). The levels of miR-27b, miR-20a, miR-24, miR-93, and miR-106b were verified by qPCR in E6/E7 silenced CaSki and SiHa cells. MiR-27b, up-regulated by E7, promoted CaSki and SiHa cell proliferation and invasion, inhibit paclitaxel-induced apoptosis. Dual-luciferase experiment confirmed miR-27b down-regulated its target gene PLK2 through the “seed regions”. The tumor suppressor PLK2 inhibited SiHa cell proliferation, reduced cell viability, and promoted paclitaxel/cisplatin -induced apoptosis. Furthermore, DGCR8 was found to mediate the up-regulation of miR-27b by HPV16 E7. Our study demonstrated that HPV16 E7 could increase DGCR8 to promote the generation of miR-27b, which accelerated cell proliferation and inhibited paclitaxel-induced cell apoptosis through down-regulating PLK2. These findings provide an insight into the interaction network of viral oncogene, miR-27b and PLK2, and support the potential strategies using antisense nucleic acid of miR-27b for therapy of cervical cancer in the future.