Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma.
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 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA 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 rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT-PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible microRNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Sho
http://orcid.org/0000-0002-3780-2993
S
Ikeda
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Akihiro
A
Kitadate
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Fumito
F
Abe
Akita Red Cross Hospital, Akita, Japan.
Hirobumi
H
Saitoh
Noshiro Kousei Medical Center, Noshiro, Japan.
Yoshihiro
Y
Michishita
Noshiro Kousei Medical Center, Noshiro, Japan.
Yoshiaki
Y
Hatano
Akita Kousei Medical Center, Akita, Japan.
Yoshinari
Y
Kawabata
Akita Kousei Medical Center, Akita, Japan.
Atsushi
A
Kitabayashi
Hiraka General Hospital, Yokote, Japan.
Kazuaki
K
Teshima
Hiraka General Hospital, Yokote, Japan.
Masaaki
M
Kume
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Naoto
N
Takahashi
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Hiroyuki
H
Tagawa
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D000099218:Interferon Regulatory Factor-4
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050835:Interferon Regulatory Factors; D008780:Methyltransferases; D035683:MicroRNAs; D000099218:Interferon Regulatory Factor-4; C497442:HIF1A protein, human; C543800:MIRN210 microRNA, human; C000605619:DIMT1 protein, human
DIMT1; IRF4; hypoxia; miR-210; multiple myeloma