MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G.

MicroRNAs have been linked to different cancer-related processes. The microRNA miR-21 appears to function as an anti-apoptosis factor in glioblastomas. However, the functional target genes of miR-21 are largely unknown in glioblastomas. In this study, bioinformatics analysis was used to identify miR-21 target sites in various genes. Luciferase activity assay showed that a number of genes involved in apoptosis, PDCD4, MTAP, and SOX5, carry putative miR-21 binding sites. Expression of PDCD4 protein correlates inversely with expression of miR-21 in a number of human glioblastoma cell lines such as T98G, A172, U87, and U251. Inhibition of miR-21 increases endogenous levels of PDCD4 in cell line T98G and over-expression miR-21 inhibits PDCD4-dependent apoptosis. Together, these results indicate that miR-21 expression plays a key role in regulating cellular processes in glioblastomas and may serve as a target for effective therapies.

[1]  P. Tran,et al.  Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Boqin Qiang,et al.  Improving the prediction of human microRNA target genes by using ensemble algorithm , 2007, FEBS letters.

[3]  David N Louis,et al.  Molecular pathology of malignant gliomas. , 2006, Annual review of pathology.

[4]  Tushar Patel,et al.  Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. , 2006, Gastroenterology.

[5]  K. Livak,et al.  Real-time quantification of microRNAs by stem–loop RT–PCR , 2005, Nucleic acids research.

[6]  Michele Pagano,et al.  S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth , 2006, Science.

[7]  J. Rodríguez-León,et al.  Analysis of the molecular cascade responsible for mesodermal limb chondrogenesis: Sox genes and BMP signaling. , 2003, Developmental biology.

[8]  Lorena Rossi,et al.  Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro. , 2007, Pharmacological research.

[9]  J. Seidenfeld,et al.  Trends in the biochemical pharmacology of 5'-deoxy-5'-methylthioadenosine. , 1982, Biochemical pharmacology.

[10]  Shuomin Zhu,et al.  miR-21-mediated tumor growth , 2007, Oncogene.

[11]  A. Krogh,et al.  Programmed Cell Death 4 (PDCD4) Is an Important Functional Target of the MicroRNA miR-21 in Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

[12]  K. Ghoshal,et al.  MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. , 2007, Gastroenterology.

[13]  W. Cho.  OncomiRs: the discovery and progress of microRNAs in cancers , 2007, Molecular Cancer.

[14]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[15]  T. Honjo,et al.  Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. , 1995, Gene.

[16]  Shuomin Zhu,et al.  MicroRNA-21 Targets the Tumor Suppressor Gene Tropomyosin 1 (TPM1)* , 2007, Journal of Biological Chemistry.

[17]  Shuji Fujita,et al.  miR-21 Gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. , 2008, Journal of molecular biology.

[18]  N. Colburn,et al.  MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene , 2008, Oncogene.

[19]  Wei Zhu,et al.  Arginine Methylation of STAT1 Modulates IFNα/β-Induced Transcription , 2001, Cell.

[20]  Torsten Werner,et al.  SoxD proteins influence multiple stages of oligodendrocyte development and modulate SoxE protein function. , 2006, Developmental cell.

[21]  A. van Hoof,et al.  Messenger RNA regulation: to translate or to degrade , 2008, The EMBO journal.

[22]  Chunhong Ma,et al.  Frequent loss of PDCD4 expression in human glioma: possible role in the tumorigenesis of glioma. , 2007, Oncology reports.

[23]  H. Allgayer,et al.  MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer , 2008, Oncogene.

[24]  Ralph Weissleder,et al.  MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. , 2007, Cancer research.

[25]  R. Göke,et al.  Programmed cell death protein 4 (pdcd4): A novel target for antineoplastic therapy? , 2003, Biology of the cell.