RRC ID 18111
著者 Matsuyama H, Suzuki HI, Nishimori H, Noguchi M, Yao T, Komatsu N, Mano H, Sugimoto K, Miyazono K.
タイトル miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma.
ジャーナル Blood
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.
巻・号 118(26)
ページ 6881-92
公開日 2011-12-22
DOI 10.1182/blood-2011-05-354654
PII S0006-4971(20)40244-7
PMID 22042699
MeSH 3' Untranslated Regions / genetics Animals Cell Line, Tumor Cell Transformation, Neoplastic / genetics* Cell Transformation, Neoplastic / immunology Cell Transformation, Neoplastic / metabolism Female GATA3 Transcription Factor / genetics GATA3 Transcription Factor / metabolism Gene Expression Regulation, Neoplastic HCT116 Cells HeLa Cells Humans Immunoblotting Immunophenotyping Interleukin-17 / immunology Interleukin-17 / metabolism* Jurkat Cells Lymphoma, Large-Cell, Anaplastic / genetics* Lymphoma, Large-Cell, Anaplastic / pathology Lymphoma, Large-Cell, Anaplastic / prevention & control Mice Mice, SCID MicroRNAs / genetics* MicroRNAs / metabolism Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Oligonucleotides, Antisense / administration & dosage Oligonucleotides, Antisense / genetics Protein-Tyrosine Kinases / genetics* Protein-Tyrosine Kinases / metabolism Reverse Transcriptase Polymerase Chain Reaction STAT3 Transcription Factor / genetics* STAT3 Transcription Factor / metabolism Th17 Cells / immunology Th17 Cells / metabolism Xenograft Model Antitumor Assays
IF 17.794
引用数 114
WOS 分野 HEMATOLOGY
リソース情報
ヒト・動物細胞 WI-38(RCB0702)