Oncotarget

Research Papers:

Proteomics analysis of bladder cancer invasion: Targeting EIF3D for therapeutic intervention

Agnieszka Latosinska, Marika Mokou, Manousos Makridakis, William Mullen, Jerome Zoidakis, Vasiliki Lygirou, Maria Frantzi, Ioannis Katafigiotis, Konstantinos Stravodimos, Marie C. Hupe, Maciej Dobrzynski, Walter Kolch, Axel S. Merseburger, Harald Mischak, Maria G. Roubelakis and Antonia Vlahou _

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Oncotarget. 2017; 8:69435-69455. https://doi.org/10.18632/oncotarget.17279

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Abstract

Agnieszka Latosinska1,2,*, Marika Mokou1,3,*, Manousos Makridakis1, William Mullen4, Jerome Zoidakis1, Vasiliki Lygirou1, Maria Frantzi2, Ioannis Katafigiotis5, Konstantinos Stravodimos5, Marie C. Hupe6, Maciej Dobrzynski7, Walter Kolch7, Axel S. Merseburger6, Harald Mischak2,4, Maria G. Roubelakis3,1 and Antonia Vlahou1

1Biotechnology Division, Biomedical Research Foundation, Academy of Athens, Athens, Greece

2Mosaiques Diagnostics GmbH, Hannover, Germany

3Laboratory of Biology, Department of Basic Medical Sciences, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

4BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom

5Department of Urology, Medical School of Athens, Laikon Hospital, Athens, Greece

6Department of Urology, Campus Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany

7Systems Biology Ireland, Conway Institute, and School of Medicine, University College Dublin, Belfield, Dublin, Ireland

*These authors contributed equally to this work

Correspondence to:

Antonia Vlahou, email: [email protected]

Keywords: EIF3D, translation, bladder cancer, tissue proteomics, RHEB

Received: January 31, 2017     Accepted: April 07, 2017     Published: April 20, 2017

ABSTRACT

Patients with advanced bladder cancer have poor outcomes, indicating a need for more efficient therapeutic approaches. This study characterizes proteomic changes underlying bladder cancer invasion aiming for the better understanding of disease pathophysiology and identification of drug targets. High resolution liquid chromatography coupled to tandem mass spectrometry analysis of tissue specimens from patients with non-muscle invasive (NMIBC, stage pTa) and muscle invasive bladder cancer (MIBC, stages pT2+) was conducted. Comparative analysis identified 144 differentially expressed proteins between analyzed groups. These included proteins previously associated with bladder cancer and also additional novel such as PGRMC1, FUCA1, BROX and PSMD12, which were further confirmed by immunohistochemistry. Pathway and interactome analysis predicted strong activation in muscle invasive bladder cancer of pathways associated with protein synthesis e.g. eIF2 and mTOR signaling. Knock-down of eukaryotic translation initiation factor 3 subunit D (EIF3D) (overexpressed in muscle invasive disease) in metastatic T24M bladder cancer cells inhibited cell proliferation, migration, and colony formation in vitro and decreased tumor growth in xenograft models. By contrast, knocking down GTP-binding protein Rheb (which is upstream of EIF3D) recapitulated the effects of EIF3D knockdown in vitro, but not in vivo. Collectively, this study represents a comprehensive analysis of NMIBC and MIBC providing a resource for future studies. The results highlight EIF3D as a potential therapeutic target.


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