MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer.
PLoS Pathog
; 16(6): e1008624, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-32555725
ABSTRACT
Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Papillomaviridae
/
RNA Neoplásico
/
Transdução de Sinais
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Transformação Celular Viral
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Neoplasias do Colo do Útero
/
Proteínas Serina-Treonina Quinases
/
Infecções por Papillomavirus
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Proteínas Supressoras de Tumor
/
MicroRNAs
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article