title: miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma.
abstract: Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immune-phenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and empowers IL-17-producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b-mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this "Th17 mimic" pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment.
authors: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan.
authors: Hironori
authors: H
authors: Matsuyama
authors: Hiroshi I
authors: HI
authors: Suzuki
authors: Hikaru
authors: H
authors: Nishimori
authors: Masaaki
authors: M
authors: Noguchi
authors: Takashi
authors: T
authors: Yao
authors: Norio
authors: N
authors: Komatsu
authors: Hiroyuki
authors: H
authors: Mano
authors: Koichi
authors: K
authors: Sugimoto
authors: Kohei
authors: K
authors: Miyazono
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D020381:Interleukin-17; C495106:LEMD1 protein, human; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases