E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer
Year: 2024
Type: article
Abstract: Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ~5% of all human cancers worldwide, including most cervical cancer cases and a growing number of anogenital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited the oncogenic phenotype in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we demonstrate that the LASP1 SH3 domain is essential for LASP1-mediated oncogenicity in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulates LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrate that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival in cervical cancer, thus identifying a potential therapeutic target in these cancers.
Source: Oncogene
Authors: Molly R. Patterson, Aniek S. Meijers, Emma L. Ryder, Louisa M. Wootton, James A. Scarth, Debra Evans, Amy L. Turner, Christopher W. Wasson, Janne E. Darell, Daisy A. Theobald, Joseph A. Cogan, Claire D. James, Miao Wang, John E. Ladbury, Iain M. Morgan, Adel Samson, Ethan L. Morgan, Andrew Macdonald
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,690
Funders: U.S. Department of Health and Human Services, Wellcome Trust, Cancer Research UK, Research Councils UK, University of Leeds, University of Sussex, University of Glasgow, National Institutes of Health, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute of Dental and Craniofacial Research, Medical Research Foundation
Awards: Defining the structural mechanism of the cellular response to DNA inter-strand crosslinks: structural characterization and inhibition of SLF1-SLF2 with its interacting partners., HPV hijacking of the epidermal growth factor receptor via its oncogenic ion channel, the E5 viroporin: a new mechanism of virus-driven pathogenesis, G1211361488, Institutional Strategic Support Fund, G1566922532, G1783852737, G2581139184, G2702851769, G3040410824, Defining the structural mechanism of the cellular response to DNA inter-strand crosslinks: structural characterization and inhibition of SLF1-SLF2 with its interacting partners., G4410256746, G4569079496, G4584296072, G4614206970, Wellcome Trust 4 year PhD Programme in The Molecular Basis of Biological Mechanisms, The TAZ transcriptional co-activator as a type specific arbiter of HPV driven cervical cancer, Development of pan- and mutation specific-Ras inhibitors through Affimer-informed small molecule design, G5080892680, G5317996124, G5444587314, Development of pan- and mutation specific-Ras inhibitors through Affimer- informed small molecule design, Institutional Strategic Support Fund, G6281500404, G6562885769, G6942171995, G7793918715, G7945897664, G813438450, G8381455261, Signalling from Receptor Tyrosine Kinases under non-stimulated conditions and the impact on cancer aggressiveness, White Rose Doctoral Training Partnership in Mechanistic Biology and its Strategic Application, G8990648099, Determining how a Werner helicase (WRN) tumor suppressor complex regulates the human papillomavirus 16 life cycle, G936870958
OpenAlex ID: W4398782054