Hypoxia‐inducible micro RNA ‐210 regulates the DIMT 1‐ IRF 4 oncogenic axis in multiple myeloma

• Published in: Cancer science Vol. 108; no. 4; pp. 641 - 652
• Main Authors: Ikeda, Sho, Kitadate, Akihiro, Abe, Fumito, Saitoh, Hirobumi, Michishita, Yoshihiro, Hatano, Yoshiaki, Kawabata, Yoshinari, Kitabayashi, Atsushi, Teshima, Kazuaki, Kume, Masaaki, Takahashi, Naoto, Tagawa, Hiroyuki
• Format: Journal Article
• Language: English
• Published: 01.04.2017
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13183

Multiple myeloma ( MM ) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti‐apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 ( IRF 4), an essential transcription factor in myeloma oncogenesis. To identify essential micro RNA s and their targets regulated under hypoxic conditions, we undertook micro RNA and c DNA microarray analyses using hypoxia‐exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR‐210 was highly upregulated and was accompanied by direct downregulation of an 18S r RNA base methyltransferase, DIMT 1. This inverse expression correlation was validated by quantitative RT ‐ PCR for primary MM samples. We further determined that DIMT 1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF 4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT 1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia‐inducible micro RNA ‐210, we identified DIMT 1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM .