title: Signal Transducer and Activator of Transcription 1 Plays a Pivotal Role in RET/PTC3 Oncogene-induced Expression of Indoleamine 2,3-Dioxygenase 1.
abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways. BRAFV600E-expressing PcCL3 cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. Moreover, we found that, the STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-κB pathway. Conversely, activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, followed by a direct tyrosine phosphorylation event, was necessary for STAT1 Tyr-701 phosphorylation. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways. Moreover, they suggest possible novel molecular targets for the abrogation of tumor microenvironment immunosuppression. The detection of those targets is becoming increasingly important to yield the full function of novel immune checkpoint inhibitors.
authors.affiliation: From the Department of Medicine, University of Perugia, 06100 Perugia; the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni.
authors.forename: Sonia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: From the Department of Medicine, University of Perugia, 06100 Perugia; the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni.
authors.forename: Elisa
authors.initials: E
authors.lastname: Menicali
authors.affiliation: From the Department of Medicine, University of Perugia, 06100 Perugia; the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni.
authors.forename: Nicole
authors.initials: N
authors.lastname: Nucci
authors.affiliation: From the Department of Medicine, University of Perugia, 06100 Perugia; the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Voce
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06100 Perugia.
authors.forename: Renato
authors.initials: R
authors.lastname: Colella
authors.affiliation: the Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II,", 80131 Naples, Italy; Istituto per l'Endocrinologia e l'Oncologia Sperimentale, CNR, 80131 Naples, Italy.
authors.forename: Rosa Marina
authors.initials: RM
authors.lastname: Melillo
authors.affiliation: the Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II,", 80131 Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Liotti
authors.affiliation: From the Department of Medicine, University of Perugia, 06100 Perugia; the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06100 Perugia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, 06100 Perugia.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: the Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II,", 80131 Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni; Departments of Surgical and Biomedical Sciences, University of Perugia, 06100 Perugia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Avenia
authors.affiliation: From the Department of Medicine, University of Perugia, 06100 Perugia; the Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, 05100 Terni. Electronic address: efisio.puxeddu@unipg.it.
authors.forename: Efisio
authors.initials: E
authors.lastname: Puxeddu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt
keywords: cancer; cell signaling; indoleamine-pyrrole 2,3-dioxygenase (IDO1); interferon regulatory factor (IRF); signal transducers and activators of transcription 1 (STAT1)