期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 6, 页码 4150-4164出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.167817
关键词
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资金
- Spanish former Ministry of Education and Science
- Ministry of Science and Innovation [SAF2006-00647, SAF2007-60780]
- Generalitat Valenciana [ACOMP 09/212]
- Genoma Espana
- Alfried Krupp von Bohlen und Halbach Foundation (Essen)
- Hella-Buhler-Foundation (Heidelberg)
- Dr. Ingrid zu Solms Foundatio (Frankfurt/Main)
- Hector Foundation (Weinheim)
- FRONTIER Excellence Initiative of the University of Heidelberg
- Federal Ministry of Education and Research (BMBF), Germany
- Walter Schulz Foundation, Munich, Germany
- European Association for Cancer Research
- Consejo Superior de Investigaciones Cientificas
MicroRNAs (miRNAs) are an emerging class of non-coding endogenous RNAs involved in multiple cellular processes, including cell differentiation. Treatment with retinoic acid (RA) results in neural differentiation of neuroblastoma cells. We wanted to elucidate whether miRNAs contribute to the gene expression changes induced by RA in neuroblastoma cells and whether miRNA regulation is involved in the transduction of the RA signal. We show here that RA treatment of SH-SY5Y neuroblastoma cells results in profound changes in the expression pattern of miRNAs. Up to 42 different miRNA species significantly changed their expression (26 up-regulated and 16 down-regulated). Among them, the closely related miR-10a and -10b showed the most prominent expression changes. Induction of miR-10a and -10b by RA also could be detected in LA-N-1 neuroblastoma cells. Loss of function experiments demonstrated that miR-10a and -10b are essential mediators of RA-induced neuroblastoma differentiation and of the associated changes in migration, invasion, and in vivo metastasis. In addition, we found that the SR-family splicing factor SFRS1 (SF2/ASF) is a target for miR-10a -and -10b in HeLa and SH-SY5Y neuroblastoma cells. We show here that changes in miR10a and -10b expression levels may regulate SFRS1-dependent alternative splicing and translational functions. Taken together, our results give support to the idea that miRNA regulation plays a key role in RA-induced neuroblastoma cell differentiation. The discovery of SFRS1 as direct target of miR-10a and -10b supports the emerging functional interaction between two post-transcriptional mechanisms, microRNAs and splicing, in the neuronal differentiation context.
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