HPV16 E6 promotes cervical cancer cell migration and invasion by downregulation of NHERF1
HPV16 E6 promotes cervical cancer cell migration and invasion by downregulation of NHERF1
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HPV16 E6通过下调NHERF1促进宫颈癌细胞迁移和侵袭
DOI：
10.1002/ijc.31876
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发表时间：
2019-04-01
影响因子：
6.4
通讯作者：
He, Junqi
中科院分区：
文献类型：
--
作者：
Wang, Qiqi;Song, Ran;He, Junqi
HPV16是导致浸润性宫颈癌的主要HPV类型。然而，与包括HPV18在内的其他类型的高危(HR)-HPV相比，HPV16具有无与伦比的致癌能力的潜在分子机制仍然不清楚。高危型HPVE6的PDZ结合基序(PBM)在宫颈癌的发生、发展中起重要作用。HPV16 E6而不是HPV18 E6通过其PBM区域与NHERF1相互作用，并诱导NHERF1降解。NHERF1通过下调ACTN4抑制细胞骨架的组装，从而抑制宫颈癌细胞在细胞和小鼠模型中的迁移和侵袭。HPV16E6通过下调NHERF1基因表达，促进肌动蛋白聚合，增加ACTN4水平，增强宫颈癌细胞的迁移和侵袭能力。对宫颈癌标本的GSEA分析还表明，HPV16E6而不是HPV18E6与肌动蛋白细胞骨架组装显著相关。HPV16E6下调NHERF1基因表达促进细胞骨架组装和细胞侵袭，是宫颈癌发生的重要原因。这些发现提供了HPV16 E6和HPV18 E6在宫颈癌发生发展中的不同机制，这可能部分解释了这两种HR-HPV致癌能力的差异。
HPV16 is the predominant type of HPV causing invasive cervical cancer. However, the underlying molecular mechanism of the unparalleled carcinogenic power of HPV16 compared to other types of high-risk (HR)-HPV including HPV18 remains elusive. The PDZ binding motif (PBM) of high-risk HPV E6 plays an important role in neoplasia and progression of cervical cancer. HPV16 E6 rather than HPV18 E6, interacted with NHERF1 by its PBM region, and induced degradation of NHERF1. NHERF1 retarded the assembly of cytoskeleton by downregulation of ACTN4, thereby inhibited the migration and invasion of cervical cancer cells in both cell and mouse model. HPV16 E6 was confirmed to enhance actin polymerization with increased ACTN4 level by downregulation of NHERF1, and result in enhanced migration and invasion of cervical cancer cells. GSEA analysis of cervical cancer specimens also showed that HPV16 E6 rather than HPV18 E6, was significantly associated with actin cytoskeleton assembly. That downregulation of NHERF1 by HPV16 E6 promoted cytoskeleton assembly and cell invasion, was an important cause in cervical cancer carcinogenesis. These findings provided the differential mechanism between HPV16 E6 and HPV18 E6 in the development and progression of cervical cancer, which may partially explain the differences of carcinogenic power between these two types of HR-HPVs.