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) |