Analysis of tripartite motif (TRIM) family gene expression in prostate cancer bone metastases

Author:

Offermann Anne1,Kang Duan1,Watermann Christian1,Weingart Anika1,Hupe Marie C2,Saraji Alireza1ORCID,Stegmann-Frehse Janine1,Kruper Rosemarie3,Schüle Roland4,Pantel Klaus5,Taubert Helge6,Duensing Stefan7,Culig Zoran8,Aigner Achim9ORCID,Klapper Wolfram10,Jonigk Danny1112,Philipp Kühnel Mark1112,Merseburger Axel S2,Kirfel Jutta1,Sailer Verena1,Perner Sven13ORCID

Affiliation:

1. Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany

2. Department of Urology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany

3. Research Center Borstel, Leibniz Lung Center, Borstel, Germany

4. Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

5. Institute for Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6. Department of Urology and Paediatric Urology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

7. Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany

8. Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

9. Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Germany

10. Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany

11. Institute of Pathology, Hannover Medical School, Hannover, Germany

12. Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, Hannover, Germany

Abstract

Abstract Tripartite motif (TRIM) family proteins are post-translational protein modifiers with E3-ubiquitin ligase activity, thereby involved in various biological processes. The molecular mechanisms driving prostate cancer (PCa) bone metastasis (BM) are incompletely understood, and targetable genetic alterations are lacking in the majority of cases. Therefore, we aimed to explore the expression and potential functional relevance of 71 TRIM members in bone metastatic PCa. We performed transcriptome analysis of all human TRIM family members and 770 cancer-related genes in 29 localized PCa and 30 PCa BM using Nanostring. KEGG, STRING and Ubibrowser were used for further bioinformatic gene correlation and pathway enrichment analyses. Compared to localized tumors, six TRIMs are under-expressed while nine TRIMs are over-expressed in BM. The differentially expressed TRIM proteins are linked to TNF-, TGFβ-, PI3K/AKT- and HIF-1-signaling, and to features such as proteoglycans, platelet activation, adhesion and ECM-interaction based on correlation to cancer-related genes. The identification of TRIM-specific E3-ligase-substrates revealed insight into functional connections to oncogenes, tumor suppressors and cancer-related pathways including androgen receptor- and TGFβ signaling, cell cycle regulation and splicing. In summary, this is the first study that comprehensively and systematically characterizes the expression of all TRIM members in PCa BM. Our results describe post-translational protein modification as an important regulatory mechanism of oncogenes, tumor suppressors, and pathway molecules in PCa progression. Therefore, this study may provide evidence for novel therapeutic targets, in particular for the treatment or prevention of BM.

Funder

German Research Foundation

University of Luebeck

China Scholarship Council

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

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