Separation of low and high grade colon and rectum carcinoma by eukaryotic translation initiation factors 1, 5 and 6

// Nicole Golob-Schwarzl 1, 2 , Caroline Schweiger 1 , Carina Koller 1 , Stefanie Krassnig 1 , Margit Gogg-Kamerer 1 , Nadine Gantenbein 1, 2 , Anna M. Toeglhofer 1 , Christina Wodlej 1, 2 , Helmut Bergler 3 , Brigitte Pertschy 3 , Stefan Uranitsch 4 , Magdalena Holter 5 , Amin El-Heliebi 6 , Julia Fuchs 6 , Andreas Punschart 7 , Philipp Stiegler 7 , Marlen Keil 8 , Jens Hoffmann 8 , David Henderson 9 , Hans Lehrach 10 , Christoph Reinhard 11 , Christian Regenbrecht 12 , Rudolf Schicho 13 , Peter Fickert 14 , Sigurd Lax 15 and Johannes Haybaeck 1, 2, 16 1 Institute of Pathology, Medical University of Graz, Graz, Austria 2 Center for Biomarker Research in Medicine, Graz, Austria 3 Institute of Molecular Biosciences, Karl-Franzens-University of Graz, Graz, Austria 4 Department of Surgery, Hospital Brothers of Charity Graz, Graz, Austria 5 Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria 6 Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria 7 Department of Surgery, Medical University of Graz, Graz, Austria 8 Experimental Pharmacology & Oncology Berlin GmbH-Berlin-Buch, Berlin, Germany 9 Bayer AG, Berlin, Germany 10 Max Planck Institute for Molecular Genetics, Berlin, Germany 11 Eli Lilly & Company, Indianapolis, USA 12 Cpo – cellular phenomics & oncology Berlin-Buch GmbH, Berlin, Germany 13 Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria 14 Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria 15 Department of Pathology, Hospital Graz South-West, Austria 16 Department of Pathology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany Correspondence to: Johannes Haybaeck, email: johannes.haybaeck@med.ovgu.de 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.