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New Pancreatic Cancer Biomarkers Eif1, Eif2d, Eif3c and Eif6 Play A

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New Pancreatic Cancer Biomarkers Eif1, Eif2d, Eif3c and Eif6 Play A ANTICANCER RESEARCH 40 : 3109-3118 (2020) doi:10.21873/anticanres.14292 New Pancreatic Cancer Biomarkers eIF1, eIF2D, eIF3C and eIF6 Play a Major Role in Translational Control in Ductal Adenocarcinoma NICOLE GOLOB-SCHWARZL 1,2 , PHILIP PUCHAS 1, MARGIT GOGG-KAMERER 1, WILKO WEICHERT 3, BENJAMIN GÖPPERT 4 and JOHANNES HAYBAECK 1,5 1Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria; 2Institute of Dermatology and Venerology, Medical University of Graz, Graz, Austria; 3Institute of Pathology, Technical University Munich, Munich, Germany; 4Department of General Pathology and Anatomy of the Pathology Institute, University Hospital Heidelberg, Heidelberg, Germany; 5Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria Abstract. Background/Aim: Pancreatic cancer is one of the Consequently, they might be useful as potential new deadliest forms of cancer and ranks among the leading causes biomarkers and therapeutic targets in PDAC. of cancer-related death worldwide. The most common histological type is ductal adenocarcinoma (PDAC), Pancreatic cancer, including ductal adenocarcinoma (PDAC), accounting for approximately 95% of cases. Deregulation of its most common manifestation, is still one of the deadliest protein synthesis has been found to be closely related to cancer. forms of cancer. It usually affects the elderly, with a 5-year The rate-limiting step of translation is initiation, which is survival rate of 5% that has not improved over the past 20 regulated by a broad range of eukaryotic translation initiation years (1). PDAC, originates from the exocrine portion of the factors (eIFs). Patients and Methods: Human PDAC samples gland and accounts for approximately 80% of cases (1). were biochemically analyzed for the expression of various eIF Compared to other hepatobiliary cancers, only little is known subunits on the protein level (immunohistochemistry, about the risk factors and molecular mechanisms underlying immunoblot analyses) in 174 cases of PDAC in comparison PDAC. Several studies have shown that alcohol and nicotine with non-neoplastic pancreatic tissue (n=10). Results: Our abuse are the main risk factors, although genetic studies have investigation revealed a significant down-regulation of four identified a large number of mutations that affect signaling specific eIF subunits, namely eIF1, eIF2D, eIF3C and eIF6. pathways (2). These genetic variations include K-RAS , the Concomitantly, the protein (immunoblot) levels of eIF1, eIF2D, tumor suppressors p53 and p16 , as well as changes in TGF- β eIF3C and eIF6 were reduced in PDAC samples as compared and WNT/NOTCH signaling (1-4). with non-neoplastic pancreatic tissue. Conclusion: Members of However, the cellular alterations promoting carcinogenesis the eIF family are of relevance in pancreatic tumor biology and still need to be investigated for their possible function as new may play a major role in translational control in PDAC. diagnostic markers, prognostic tools and novel therapeutic targets. Translation, the process of protein synthesis crucially needed for cellular homeostasis, is subdivided into four major steps: This article is freely accessible online. initiation, elongation, termination and ribosome recycling. Initiation constitutes the rate-limiting step and is concerted by Correspondence to: Prof. Johannes Haybaeck, MD, Ph.D., an abundance of eukaryotic translation initiation factors (eIFs), Department of Pathology, Neuropathology and Molecular acting in different ways to generate the fully functional Pathology, Medical University of Innsbruck, Müllerstraße 44, A- ribosomal apparatus with its associated interaction partners, 6020 Innsbruck, Austria. Tel: +43 0512900371300, Fax: +49 3916715818, e-mail: [email protected] such as the formyl-methionine-tRNA and the consecutively translated messenger RNA (mRNA) (5). Briefly, translation Key Words: Pancreatic cancer, eukaryotic translation initiation initiation starts with the formation of the 43S-preinitiation factors, PI3K/AKT/mTOR pathway, biomarker. complex, consisting of the 40S ribosomal subunit, the ternary 3109 ANTICANCER RESEARCH 40 : 3109-3118 (2020) complex (which is composed of the initiating methionyl-tRNA Table I. Clinical and pathological characteristics of 174 patients with bound to eIF2-GTP), eIF1, eIF1A and eIF3. This assembly pancreatic cancer. For each biochemically assessed PDAC patient, the clinical and pathological characteristics, including sex, age, TNM, consecutively scans the mRNA for the first start codon (AUG) stage and the presence of positive lymph nodes, are listed. in the 5´ untranslated region (UTR), leading to codon- anticodon interaction assisted by eIF1 and eIF1A. The scanning Total (%) Male (%) Female (%) process is further assisted by the heterotrimeric eIF4F complex (eIF4A, eIF4E and eIF4G). Binding to the matching start n 174 (100) 98 (56.3) 76 (43.7) Mean age 64.14 62.44 66.33 codon leads to eIF2-GTP hydrolysis and dissociation of the pT respective eIF2-GDP. Ribosomal subunit joining is mediated 1/2 35 (20.1) 15 (15.3) 20 (26.3) through eIF5B, forming the fully functional ribosome (5). 3/4 139 (79.9) 83 (84.7) 56 (73.7) Dysfunction in translational control is an important pN downstream endpoint of oncogenic pathways, such as the 0 42 (24.1) 22 (22.4) 20 (26.3) 1 132 (75.9) 76 (77.6) 56 (73.7) PI3K/AKT/mTOR and RAS/RAF/MAPK pathways, which pM support cellular transformation and tumor development (6). 0 168 (96.6) 93 (94.9) 75 (98.7) In normal cells, these pathways operate as sensors of nutrient 1 6 (3.4) 5 (5.1) 1 (1.3) availability, stress or energy, adapting ribosome production Grading and gene expression to the cellular conditions. eIFs have 1 7 (4) 4 (4.1) 3 (3.9) 2 92 (52.9) 51 (52) 41 (54) recently been discovered to be involved in tumor 3 75 (43.1) 43 (43.9) 32 (42.1) development in a variety of malignancies (6, 7), and have therefore been suggested as potential therapeutic targets with some substances currently under preclinical and early clinical investigation (7-10). Dysregulation of translation initiation Immunohistochemistry. IHC was performed on a Ventana and its interaction with the PI3K/AKT/mTOR signaling Immunostainer XT (Ventana Medical Systems, Tucson, AZ, USA) pathway are just starting to be understood in pancreatic by heat-induced epitope retrieval (HIER) in cell conditioning cancer. Previously described alterations include up-regulation solution for 30 min and an ultra-VIEW universal DAB Detection of eIF3A, eIF4E and eIF5A, as well as down-regulation of Kit (Ventana Medical Systems, Tucson, AZ, USA). The primary eIF3F (11-16). However, the molecular mechanism antibodies were incubated for 30 minutes using different dilutions regulating eIFs in tumor biology is still not fully understood. (Table II). Each core was semi-quantitatively scored, and an intensity score was defined as follows: 0=no staining, 1=weak To address this issue, we investigated the involvement of staining, 2=moderate staining and 3=strong staining. Additionally, the PI3K/AKT/mTOR signaling cascade and various eIF the percentage of stained tumor cells was determined (0-100%) and subunits, focusing on PDAC. For this purpose, we used assigned to 5 groups, 0=0%, 1=1-49%, 3=50-79% and 4= 80-100%. protein analyses, immunohistochemistry and immunoblotting The intensity score (0-3) was then multiplied by the percentage to characterize the expression pattern of the mTOR signaling score (0-4), and the values obtained were subdivided as follows: members and various eIF subunits. 0=no staining, 1-4=weak staining, 5-8=moderate staining, 9- 12=strong staining, and displayed in stacked plots. Materials and Methods Human pancreatic cancer patient samples. Human pancreas cancer samples (n=56) and non-neoplastic tissue (NNT) (n=56) were Ethics statement. The collection and use of human derived pancreas provided by the Department of Pathology, Medical University of specimens were approved by the Ethics Committee of the Medical Magdeburg, Germany. Informed consent was obtained from all University of Graz, Graz, Austria, according to the ethical guidelines patients. All samples were acquired during surgery, immediately of the 1975 Declaration of Helsinki (EK 28-294 ex 15/16). All samples snap frozen in liquid nitrogen, and stored at –80˚C until protein or and medical data used in this study were irreversibly anonymized, and RNA extraction. their clinical and pathological data are listed in Tables I and II. Protein extraction and western blot analysis. To prepare protein Tissue microarray (TMA). A total of 174 formalin-fixed, paraffin- lysates, frozen tissue samples were homogenized with a MagNA embedded patient samples were retrospectively collected from the Lyser homogenizer (Roche Diagnostics, Risch-Rotkreuz, Switzerland) Institute of Pathology, Technical University Munich, Germany. and lysed in Nonidet-P40-based lysis buffer (0.05 M Tris-HCl, 0.15 Hematoxylin-eosin stained (H/E) slides were reviewed by experienced, M NaCl, 0.5% NP-40, 0.1 mM pefabloc, 1 mM DTT, complete mini board certified pathologists (J.H. and I.B.), who confirmed the EDTA-free, PhosSTOP (Roche Austria GmbH, Vienna, Austria). diagnosis and identified the areas of tumor and non-neoplastic tissue Protein concentrations were determined using Bradford protein assay for each tissue microarray core. Tissue cylinders of 1.2 mm in (Biorad Protein Assay Dye Reagent; BioRad Laboratories GmbH, diameter were punched out from the
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