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E6 介导的 JNK 激活促进 EGFR 信号通路,进而促进宫颈癌的增殖和病毒癌蛋白表达。

E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer.

机构信息

School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK.

Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, LS2 9JT, UK.

出版信息

Cell Death Differ. 2021 May;28(5):1669-1687. doi: 10.1038/s41418-020-00693-9. Epub 2020 Dec 10.

Abstract

Human papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

摘要

人乳头瘤病毒(HPV)是全球恶性肿瘤的主要病因之一,约占所有人类癌症的 5%,包括几乎所有宫颈癌病例以及越来越多的肛门生殖器和口腔癌症。HPV 诱导的恶性肿瘤主要由病毒癌基因 E6 和 E7 驱动,这些基因操纵宿主细胞途径以增加细胞增殖并增强细胞存活,最终使受感染的细胞易于恶性转化。因此,更详细地了解 HPV 相关疾病中的病毒-宿主相互作用有可能确定新的治疗靶标。在这里,我们发现 c-Jun N 端激酶(JNK)信号通路在宫颈疾病和宫颈癌中被激活。HPV E6 癌基因以需要 E6 PDZ 结合基序的方式诱导 JNK1/2 磷酸化。我们表明,使用小分子抑制剂阻断 JNK1/2 信号或敲低经典 JNK 底物 c-Jun,可减少宫颈癌细胞的增殖并诱导细胞凋亡。我们进一步证明,这种表型至少部分是由 JNK 依赖性激活 EGFR 信号通过增加 EGFR 和 EGFR 配体 EGF 和 HB-EGF 的表达驱动的。JNK/c-Jun 信号促进了宫颈癌细胞的侵袭潜力,并需要上皮间质转化(EMT)相关转录因子 Slug 和间质标志物 Vimentin 的表达。此外,JNK/c-Jun 信号对于 HPV E6 和 E7 的组成型表达是必需的,这对于宫颈癌细胞的生长和存活至关重要。总之,这些数据表明 EGFR 信号通路和 HPV E6/E7 表达之间存在正反馈回路,确定了一种调节机制,其中 HPV 驱动 EGFR 信号以促进增殖、存活和 EMT。因此,我们的研究确定了一个新的治疗靶标,可能有益于宫颈癌的治疗。

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