Novel diagnostic and prognostic prostate cancer biomarkers buffer the translational burden of neoplastic transformation


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Jonathan Kay Kay1,Lars Egevad2,Anne Warren3,Amanda Seipel2,Charlie Massie4,Fredrik Wiklund2,Benjamin Thomas5,Steve Hawkins6,Hayley Luxton1,Ian Mills7,Peter Wiklund2,Benjamin Simpson1,Jodi Miller5,Suraj Menon5,Gabrielle Fisher2,Susan Heavy8,Hayley Pye1,Jack Cuzick9,David Neal10,Hayley Whitaker1
1University college london,2Karolinska Institute,3Cambridge University,4University of Cambridge,5CRUK cambridge,6CRUK,7Centre for Molecular Medicine Norway,8university college london,9CRUK Queen Mary University of London,10Oxford university

Abstract

Background

The cellular transformation associated with tumorigenesis introduces metabolic and translational pressures that must be overcome if cancer cells are to survive. Excessive levels of newly translated proteins are processed by inducing the stress response pathway, autophagy or secretion to prevent them becoming toxic to the cell. BI-015 and BI-016 are vesicle sorting proteins which can both be used as diagnostic biomarkers of prostate cancer.

Method

BI-015 and BI-016 expression was quantified using immunohistochemistry in three independent tissue microarrays. A stably knocked-down shBI-015-LNCaP cell line was characterised using several cellular assays including: protein translation, proliferation, colony formation and migration assays to elucidate the protein’s function. Network analysis revealed an association of BI-015 with protein translation, lysosome and stress response.

Results

BI-015 expression was increased in several tumour types including: liver, colon, and stomach. The highest expression of BI-015 and BI-016 was in the epithelial cells of prostate tumours with minimal expression in benign tissue. Expression of both proteins increased with Gleason Grade. BI-015 expression predicted patient outcome, with high expression doubling the likelihood of recurrence within 5 years following radical prostatectomy (HR=2.2, p-value=0.01). BI-015 localised to vesicular structures that co-localised and fused with components of the Golgi apparatus and Lamp2 positive lysosomes. ShBI-015-LNCaP cells showed significantly reduced proliferation, colony formation, protein translation and migration. Thapsigargin treatment demonstrated that BI-015 also regulates cell stress response pathways. Knockdown of BI-015 reduced PSA secretion and its expression also reflects the hormone status of patients and is indirectly androgen regulated via ETV1.

Conclusion

BI-015 is over expressed in multiple cancers and is a novel predictive and diagnostic biomarker of prostate cancer. BI-015 is regulated by the androgen regulated gene, ETV-1 and regulates protein translation and PSA secretion as well as promoting a more aggressive phenotype.