CUL2 overexpression driven by CUL2/E2F1/miR-424 regulatory loop promotes HPV16 E7 induced cervical carcinogenesis.
CUL2 overexpression driven by CUL2/E2F1/miR-424 regulatory loop promotes HPV16 E7 induced cervical carcinogenesis.
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CUL2/E2F1/miR-424调节环驱动的CUL2过表达促进HPV16 E7诱导的宫颈癌发生
DOI：
10.18632/oncotarget.9127
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Xu J;Fang Y;Wang X;Wang F;Tian Q;Li Y;Xie X;Cheng X;Lu W
已有研究表明，HPV 16 E7在诱导宫颈癌发生过程中能与支架蛋白CUL 2结合，而其他基因型则不能，但CUL 2本身的表达水平、相关调控机制及潜在致癌性尚不清楚。我们发现CUL 2在HPV 16阳性的宫颈癌细胞和组织中特异性过表达，并且CUL 2的表达沿着宫颈病变的进展而显著增加，并且与HPV 16 E7呈正相关。CUL 2敲低减缓了小鼠模型中异种移植肿瘤的生长。重要的是，CUL 2特异性结合HPV 16 E7，但不结合HPV 18 E7。此外，CUL 2作为miR-424的直接靶点，miR-424的表达受到抑制，E2 F转录因子1（E2 F1）抑制miR-424的表达，CUL 2与E2 F1结合并促进E2 F1的表达。我们的研究结果表明HPV 16阳性宫颈癌细胞中存在CUL 2、E2 F1和miR-424之间的调节环。我们的研究结果表明，E7招募CUL 2，由CUL 2/E2 F1/miR-424调控环驱动，过表达并加速HPV 16诱导的宫颈癌发生。我们的研究结果可能可以作为高危HPV基因型中HPV 16具有最强宫颈致癌性的临床现象的解释之一。
It has been shown that HPV16 E7, but not other genotypes, can bind to scaffold protein CUL2 during inducing cervical carcinogenesis, but the expression level, associated regulating mechanism, and potential carcinogenicity of CUL2 itself is still unknown as yet. Here, we demonstrated that CUL2 was specifically overexpressed in HPV16 positive cervical cancer cells and tissues, and CUL2 expression was significantly increased along with the cervical lesion progression and positively correlated with HPV16 E7. CUL2 knockdown slowed the growth of xenograft tumors in mouse models. Importantly, CUL2 specifically bound to HPV16 E7, but not HPV18 E7. Moreover, CUL2 acted as a direct target of miR-424, and reversely suppressed miR-424; E2F transcription factor 1 (E2F1) suppressed miR-424 expression; CUL2 bound to E2F1 and promoted E2F1 expression. Our results indicate the existence of a regulatory loop among CUL2, E2F1, and miR-424 in HPV16 positive cervical cancer cells. Our results suggest that E7 recruited CUL2, driven by CUL2/E2F1/miR-424 regulatory loop, is overexpressed and accelerates HPV16-induced cervical carcinogenesis. Our findings may serve as one of the explanations for a clinical phenomenon that HPV16 possesses the strongest cervical carcinogenicity among high-risk HPV genotypes.
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