E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer.
E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer.
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DOI：
10.1038/s41418-020-00693-9
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发表时间：
2021-05
影响因子：
12.4
通讯作者：
Macdonald A
中科院分区：
文献类型：
--
作者：
Morgan EL;Scarth JA;Patterson MR;Wasson CW;Hemingway GC;Barba-Moreno D;Macdonald A
人乳头瘤病毒（HPV）是全球恶性肿瘤的主要原因，占所有人类癌症的约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。HPV诱导的恶性肿瘤主要由病毒致癌基因E6和E7驱动，其操纵宿主细胞途径以增加细胞增殖并增强细胞存活，最终使感染的细胞易于恶性转化。因此，对HPV相关疾病中病毒-宿主相互作用的更详细了解提供了确定新的治疗靶点的可能性。在这里，我们确定c-Jun N-末端激酶（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JNK 1/2磷酸化。我们发现，使用小分子抑制剂阻断JNK 1/2信号传导，或敲低经典JNK底物c-Jun，可降低宫颈癌细胞的细胞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通过EGFR和EGFR配体EGF和HB-EGF的表达增加而由EGFR信号传导的JNK依赖性激活驱动的。JNK/c-Jun信号传导促进了宫颈癌细胞的侵袭潜力，并且是上皮向间质转化（EMT）相关转录因子Slug和间质标志物波形蛋白表达所必需的。此外，JNK/c-Jun信号传导是HPV E6和E7的组成型表达所必需的，这对宫颈癌细胞的生长和存活是必不可少的。总之，这些数据证明了EGFR信号传导途径和HPV E6/E7表达之间的正反馈回路，确定了HPV驱动EGFR信号传导以促进增殖、存活和EMT的调节机制。因此，我们的研究已经确定了一种新的治疗靶点，可能有利于宫颈癌的治疗。
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.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
11.5
作者：
Brand, Toni M.;Hartmann, Stefan;Grandis, Jennifer R.
通讯作者：
Grandis, Jennifer R.
影响因子：
6.4
作者：
Das, Dipon;Bristol, Molly L.;Morgan, Iain M.
通讯作者：
Morgan, Iain M.
影响因子：
5.4
作者：
Delury CP;Marsh EK;James CD;Boon SS;Banks L;Knight GL;Roberts S
通讯作者：
Roberts S
影响因子：
7.7
作者：
Girnius N;Edwards YJ;Garlick DS;Davis RJ
通讯作者：
Davis RJ