miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma

6533b82efe1ef96bd1293d38

RESEARCH PRODUCT

miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma

Marco Rossi Paola Critelli Caterina Riillo Nicola Amodio Bernardo Bertucci Cirino Botta Francesco Conforti Domenica Scumaci Bruno Paiva Sarai Sarvide Marco Gaspari Pierosandro Tagliaferri Maria Eugenia Gallo Cantafio Michelangelo Iannone Pierfrancesco Tassone Pierfrancesco Tassone Emanuela Altomare Maria Teresa Di Martino Daniele Caracciolo Nicoletta Polerà Mariamena Arbitrio Domenico Taverna

subject

0301 basic medicine Male Cancer Research Bone disease Apoptosis Bone Neoplasms Nod Mice SCID Bone Neoplasm T-Lymphocytes Regulatory Th17 Cell 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation gammopathies Mice Inbred NOD medicine Tumor Cells Cultured Tumor Microenvironment Biomarkers Tumor Animals Humans Multiple myeloma Cell Proliferation Chemistry Cell growth Animal Apoptosi Hematology medicine.disease Prognosis Xenograft Model Antitumor Assays In vitro Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Case-Control Studies Cancer research Th17 Cells Bone marrow Antagonism Case-Control Studie Multiple Myeloma

description

Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.

year	journal	country	edition	language
2020-07-06

10.1038/s41375-020-0947-1 http://hdl.handle.net/10447/513411