title: Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells.
abstract: MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle-arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. anna@pehserl.com.|Research Unit of Non-Coding RNA and Genome Editing in Cancer, Medical University of Graz, 8010 Graz, Austria. anna@pehserl.com.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Pehserl
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. anna.lena.ress@gmail.com.|Research Unit of Non-Coding RNA and Genome Editing in Cancer, Medical University of Graz, 8010 Graz, Austria. anna.lena.ress@gmail.com.
authors.forename: Anna Lena
authors.initials: AL
authors.lastname: Ress
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. stefanie.stanzer@medunigraz.at.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stanzer
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. margit.resel@medunigraz.at.|Research Unit of Non-Coding RNA and Genome Editing in Cancer, Medical University of Graz, 8010 Graz, Austria. margit.resel@medunigraz.at.
authors.forename: Margit
authors.initials: M
authors.lastname: Resel
authors.affiliation: Department of Phoniatrics, ENT University Hospital, Medical University, 8010 Graz, Austria. michael.karbiener@medunigraz.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Karbiener
authors.affiliation: Institute of Pathology, Medical University of Graz, 8010 Graz, Austria. elke.stadelmeyer@medunigraz.at.
authors.forename: Elke
authors.initials: E
authors.lastname: Stadelmeyer
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. verena.stiegelbauer@medunigraz.at.|Research Unit of Non-Coding RNA and Genome Editing in Cancer, Medical University of Graz, 8010 Graz, Austria. verena.stiegelbauer@medunigraz.at.
authors.forename: Verena
authors.initials: V
authors.lastname: Stiegelbauer
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. armin.gerger@medunigraz.at.
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.affiliation: Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. ch.mayr@salk.at.|Department of Internal Medicine I, Salzburger Landeskliniken, Paracelsus Medical University, 5020 Salzburg, Austria. ch.mayr@salk.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Mayr
authors.affiliation: Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. marcel.scheideler@helmholtz-muenchen.de.|Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, 69120 Heidelberg, Germany. marcel.scheideler@helmholtz-muenchen.de.|Molecular Metabolic Control, Medical Faculty, Technical University Munich, 85764 Munich, Germany. marcel.scheideler@helmholtz-muenchen.de.|German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. marcel.scheideler@helmholtz-muenchen.de.
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheideler
authors.affiliation: Department of Urology, Medical University of Graz, 8010 Graz, Austria. georg.hutterer@medunigraz.at.
authors.forename: Georg C
authors.initials: GC
authors.lastname: Hutterer
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. thomas.bauernhofer@medunigraz.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauernhofer
authors.affiliation: Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. t.kiesslich@salk.at.|Department of Internal Medicine I, Salzburger Landeskliniken, Paracelsus Medical University, 5020 Salzburg, Austria. t.kiesslich@salk.at.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiesslich
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria. martin.pichler@medunigraz.at.|Research Unit of Non-Coding RNA and Genome Editing in Cancer, Medical University of Graz, 8010 Graz, Austria. martin.pichler@medunigraz.at.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. martin.pichler@medunigraz.at.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000077157:Sorafenib
chemical_list: C117307:KRAS protein, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D016283:Proto-Oncogene Proteins p21(ras)
keywords: colorectal cancer; miRNA; sorafenib