Downregulation of microRNAs‐143 and ‐145 in B‐cell malignancies

Recently, it has been found that inappropriate expression of microRNAs (miRNAs) is strongly associated with carcinogenesis. In this study, we demonstrated that the expression of miRNAs (miRs) ‐143 and ‐145, the levels of which were previously shown to be reduced in colon cancers and various kinds of established cancer cell lines, was also decreased in most of the B‐cell malignancies examined, including chronic lymphocytic leukemias (CLL), B‐cell lymphomas, Epstein‐Barr virus (EBV)‐transformed B‐cell lines, and Burkitt lymphoma cell lines. All samples from 13 CLL patients and eight of nine B‐cell lymphoma ones tested exhibited an extremely low expression of miRs‐143 and ‐145. The expression levels of miRs‐143 and ‐145 were consistently low in human Burkitt lymphoma cell lines and were inversely associated with the cell proliferation observed in the EBV‐transformed B‐cell lines. Moreover, the introduction of either precursor or mature miR‐143 and ‐145 into Raji cells resulted in a significant growth inhibition that occurred in a dose‐dependent manner and the target gene of miRNA‐143 was determined to be ERK5, as previously reported in human colon cancer DLD‐1 cells. Taken together, these findings suggest that miRs‐143 and ‐145 may be useful as biomarkers that differentiate B‐cell malignant cells from normal cells and contribute to carcinogenesis in B‐cell malignancies by a newly defined mechanism. (Cancer Sci 2007; 98: 1914–1920)

[1]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[2]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[3]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[4]  Satoko Nishimoto,et al.  MAPK signalling: ERK5 versus ERK1/2 , 2006, EMBO reports.

[5]  D. Bartel,et al.  Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs , 2004, Nature Reviews Genetics.

[6]  V. Ambros,et al.  An Extensive Class of Small RNAs in Caenorhabditis elegans , 2001, Science.

[7]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Y. Li,et al.  Incorporating structure to predict microRNA targets. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Croce,et al.  MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[11]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[12]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Brian S. Roberts,et al.  The colorectal microRNAome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Tuschl,et al.  Identification of Novel Genes Coding for Small Expressed RNAs , 2001, Science.

[15]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Alessandro Fatica,et al.  A Minicircuitry Comprised of MicroRNA-223 and Transcription Factors NFI-A and C/EBPα Regulates Human Granulopoiesis , 2005, Cell.

[17]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[18]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[19]  C. Croce,et al.  miRNAs, Cancer, and Stem Cell Division , 2005, Cell.

[20]  Muller Fabbri,et al.  A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. , 2005, The New England journal of medicine.

[21]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[23]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[24]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[25]  Phillip D. Zamore,et al.  Ribo-gnome: The Big World of Small RNAs , 2005, Science.

[26]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[27]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[28]  Ravi Jain,et al.  MicroRNA-143 Regulates Adipocyte Differentiation* , 2004, Journal of Biological Chemistry.

[29]  Y. Yatabe,et al.  A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. , 2005, Cancer research.

[30]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[31]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[32]  R. Shiekhattar,et al.  MicroRNA biogenesis and cancer. , 2005, Cancer research.

[33]  M. Cobb,et al.  Identification of Substrates and Regulators of the Mitogen-activated Protein Kinase ERK5 Using Chimeric Protein Kinases* , 1998, The Journal of Biological Chemistry.

[34]  Wayne Tam,et al.  Accumulation of miR-155 and BIC RNA in human B cell lymphomas. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Y. Akao,et al.  MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers. , 2006, Oncology reports.

[36]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[37]  L. Lim,et al.  An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans , 2001, Science.

[38]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[39]  Mariette Schrier,et al.  A Genetic Screen Implicates miRNA-372 and miRNA-373 As Oncogenes in Testicular Germ Cell Tumors , 2006, Cell.

[40]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.