Journal Article

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

Blair, G. Eric, Morgan, Ethan L., Griffin, Stephen, Wasson, Christopher W., Macdonald, Andrew, Ryder, Emma L., Lee, Siu Yi, Whitehouse, Adrian, Harper, Katherine L., Li, Yigen, Patterson, Molly R.

2020

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Anogenital / Biology and life sciences / Cancer / Cell Line, Tumor / Cell proliferation / Cell Transformation, Viral / Cellular biology / Cervical cancer / Female / Funding / Gene expression / Gene Expression Regulation, Neoplastic / Head & neck cancer / Head and neck / Homeostasis / Human papilloma viruses / Human papillomavirus / Humans / Intracellular Signaling Peptides and Proteins / Kinases / Localization / Malignancy / Medical prognosis / Medicine and Health Sciences / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Molecular biology / Oncogene Proteins, Viral - genetics / Oncogene Proteins, Viral - metabolism / Papillomaviridae / Papillomaviridae - genetics / Papillomaviridae - metabolism / Papillomavirus Infections - genetics / Papillomavirus Infections - metabolism / Papillomavirus Infections - pathology / Papillomavirus Infections - virology / Pathogenesis / Phosphorylation / Protein expression / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Research and analysis methods / RNA, Neoplasm - genetics / RNA, Neoplasm - metabolism / Signal Transduction / Target recognition / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor cell lines / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumors / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - metabolism / Uterine Cervical Neoplasms - pathology / Uterine Cervical Neoplasms - virology / Viruses / YAP-Signaling Proteins / Yes-associated protein