Journal Article

E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer

Scarth, James A., Wang, Miao, Macdonald, Andrew, Ryder, Emma L., Ladbury, John E., Darell, Janne E., Turner, Amy L., Meijers, Aniek S., Cogan, Joseph A., Morgan, Iain M., Evans, Debra, Patterson, Molly R., Wootton, Louisa M., James, Claire D., Morgan, Ethan L., Theobald, Daisy A., Wasson, Christopher W., Samson, Adel

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/51 / 13/89 / 13/95 / 3' Untranslated regions / 631/67/1517/1371 / 631/67/1858 / 82/29 / Actin / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / Anogenital / Antiviral agents / Antiviral drugs / Apoptosis / Cell Biology / Cell Line, Tumor / Cell proliferation / Cell Proliferation - genetics / Cell survival / Cervical cancer / Cytoskeletal Proteins - genetics / Cytoskeletal Proteins - metabolism / Female / Gene expression / Gene Expression Regulation, Neoplastic / Human Genetics / Human papillomavirus / Humans / Internal Medicine / LIM Domain Proteins - genetics / LIM Domain Proteins - metabolism / Malignancy / Medicine / Medicine & Public Health / Mice / MicroRNAs - genetics / Oncology / Oral cancer / Papillomavirus E7 Proteins - genetics / Papillomavirus E7 Proteins - metabolism / Papillomavirus Infections - complications / Papillomavirus Infections - genetics / Papillomavirus Infections - pathology / Papillomavirus Infections - virology / Phenotypes / Post-transcription / Therapeutic targets / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - pathology / Uterine Cervical Neoplasms - virology