Research Papers:
Separation of low and high grade colon and rectum carcinoma by eukaryotic translation initiation factors 1, 5 and 6
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Abstract
Nicole Golob-Schwarzl1,2, Caroline Schweiger1, Carina Koller1, Stefanie Krassnig1, Margit Gogg-Kamerer1, Nadine Gantenbein1,2, Anna M. Toeglhofer1, Christina Wodlej1,2, Helmut Bergler3, Brigitte Pertschy3, Stefan Uranitsch4, Magdalena Holter5, Amin El-Heliebi6, Julia Fuchs6, Andreas Punschart7, Philipp Stiegler7, Marlen Keil8, Jens Hoffmann8, David Henderson9, Hans Lehrach10, Christoph Reinhard11, Christian Regenbrecht12, Rudolf Schicho13, Peter Fickert14, Sigurd Lax15 and Johannes Haybaeck1,2,16
1Institute of Pathology, Medical University of Graz, Graz, Austria
2Center for Biomarker Research in Medicine, Graz, Austria
3Institute of Molecular Biosciences, Karl-Franzens-University of Graz, Graz, Austria
4Department of Surgery, Hospital Brothers of Charity Graz, Graz, Austria
5Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
6Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria
7Department of Surgery, Medical University of Graz, Graz, Austria
8Experimental Pharmacology & Oncology Berlin GmbH-Berlin-Buch, Berlin, Germany
9Bayer AG, Berlin, Germany
10Max Planck Institute for Molecular Genetics, Berlin, Germany
11Eli Lilly & Company, Indianapolis, USA
12Cpo – cellular phenomics & oncology Berlin-Buch GmbH, Berlin, Germany
13Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
14Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
15Department of Pathology, Hospital Graz South-West, Austria
16Department of Pathology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
Correspondence to:
Johannes Haybaeck, email: [email protected]
Keywords: colorectal carcinoma; liver metastases; eukaryotic translation initiation factors; PI3K/AKT/mTOR pathway
Received: January 05, 2017 Accepted: July 31, 2017 Published: September 05, 2017
ABSTRACT
Colorectal cancer (CRC) is the third most common cause of cancer related death worldwide. Furthermore, with more than 1.2 million cases registered per year, it constitutes the third most frequent diagnosed cancer entity worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Eukaryotic translation initiation factors (eIFs) are involved in the regulation of protein synthesis and are functionally linked to the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway.
The identification of factors accounting for colorectal carcinoma (CRC) development is a major gap in the field. Besides the importance of eIF3 subunits and the eIF4 complex, eIF1, eIF5 and eIF6 were found to be altered in primary and metastatic CRC. We observed significant difference in the expression profile between low and high grade CRC. eIF1, eIF5 and eIF6 are involved in translational control in CRC. Our findings also indicate a probable clinical impact when separating them into low and high grade colon and rectum carcinoma.
eIF and mTOR expression were analysed on protein and mRNA level in primary low and high grade colon carcinoma (CC) and rectum carcinoma (RC) samples in comparison to non-neoplastic tissue without any disease-related pathology. To assess the therapeutic potential of targeting eIF1, eIF5 and eIF6 siRNA knockdown in HCT116 and HT29 cells was performed. We evaluated the eIF knockdown efficacy on protein and mRNA level and investigated proliferation, apoptosis, invasion, as well as colony forming and polysome associated fractions.
These results indicate that eIFs, in particular eIF1, eIF5 and eIF6 play a major role in translational control in colon and rectum cancer.
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