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

English version

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: https://doi.org/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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