MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer


Autoři: Ethan L. Morgan aff001;  Molly R. Patterson aff001;  Emma L. Ryder aff001;  Siu Yi Lee aff001;  Christopher W. Wasson aff001;  Katherine L. Harper aff001;  Yigen Li aff001;  Stephen Griffin aff002;  G. Eric Blair aff001;  Adrian Whitehouse aff001;  Andrew Macdonald aff001
Působiště autorů: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, U.K, United Kingdom aff001;  Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, U.K, United Kingdom aff002;  Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K, United Kingdom aff003
Vyšlo v časopise: MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008624
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008624

Souhrn

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.

Klíčová slova:

Cell proliferation – Cervical cancer – Gene expression – HeLa cells – Human papillomavirus – Human papillomavirus infection – Protein expression – Small interfering RNAs


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