BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

Loveridge, C. J. et al. (2020) BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration. Oncogene, 39, pp. 1797-1806. (doi: 10.1038/s41388-019-1106-x) (PMID:31740786) (PMCID:PMC7033044)

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Abstract

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten BRF1 ) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten BRF1 tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK (A15151, A10419 and A17196; HYL) and Prostate Cancer UK (PG10-10; HYL). SS's PhD was supported by Medical Research Council Clinical Research Training Fellowship. NAN's PhD was sponsored by Ministry of Higher Education, Malaysia and SLAI Fellowship from University of Malaya.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmad, Dr Imran and Leung, Professor Hing and Blyth, Professor Karen and Bryson, Miss Sheila and Salji, Dr Mark and Mitchell, Mrs Louise and Nixon, Mr Colin and Lilla, Dr Sergio and Campbell, Dr Kirsteen and Edwards, Professor Joanne and Ntala, Dr Chara and Slater, Dr Sarah and Zanivan, Professor Sara Rossana and Repiscak, Dr Peter and Strathdee, Dr Douglas and Patel, Dr Rachana and Goodyear, Professor Carl and Loveridge, Dr Carolyn
Authors: Loveridge, C. J., Slater, S., Campbell, K. J., Nam, N. A., Knight, J., Ahmad, I., Hedley, A., Lilla, S., Repiscak, P., Patel, R., Salji, M., Fleming, J., Mitchell, L., Nixon, C., Strathdee, D., Neilson, M., Ntala, C., Bryson, S., Zanivan, S. R., Edwards, J., Robson, C. N., Goodyear, C. S., Blyth, K., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Oncogene
Publisher:Springer Nature
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:18 November 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Oncogene 39:1797–1806
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
165323Synergistic interaction between Sprouty2 loss and PI3K/AKT activation in prostate carcinogenesisHing LeungProstate Cancer UK (PROSCANU)PG10-10CS - Clinical Research Garscube