title: microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome.
abstract: BACKGROUND
  Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs.
  
  
  METHODS
  The expression levels of microRNAs were quantified using microarray and RT-qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples.
  
  
  RESULTS
  We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival.
  
  
  CONCLUSIONS
  Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST.
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [2] Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Akçakaya
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [2] Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Caramuta
authors.affiliation: 1] Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Department of Breast and Endocrine Surgery, Endocrine and Sarcoma Surgery Unit, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Åhlen
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [2] Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ghaderi
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Berglund
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [2] Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Östman
authors.affiliation: 1] Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Department of Breast and Endocrine Surgery, Endocrine and Sarcoma Surgery Unit, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Bränström
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [2] Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Larsson
authors.affiliation: 1] Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden [2] Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden.
authors.forename: W-O
authors.initials: WO
authors.lastname: Lui
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D006801:Humans; D000068877:Imatinib Mesylate; D035683:MicroRNAs / Q000502:physiology*; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C531888:MIRN125 microRNA, human; C550735:MIRN301A microRNA, human; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C422224:PTPN18 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor