Expression profiling identifies microRNA signature in pancreatic cancer

microRNAs are functional, 22 nt, noncoding RNAs that negatively regulate gene expression. Disturbance of microRNA expression may play a role in the initiation and progression of certain diseases. A microRNA expression signature has been identified that is associated with pancreatic cancer. This has been accomplished with the application of real‐time PCR profiling of over 200 microRNA precursors on specimens of human pancreatic adenocarcinoma, paired benign tissue, normal pancreas, chronic pancreatitis and nine pancreatic cancer cell lines. Hierarchical clustering was able to distinguish tumor from normal pancreas, pancreatitis and cell lines. The PAM algorithm correctly classified 28 of 28 tumors, 6 of 6 normal pancreas and 11 of 15 adjacent benign tissues. One hundred microRNA precursors were aberrantly expressed in pancreatic cancer or desmoplasia (p < 0.01), including microRNAs previously reported as differentially expressed in other human cancers (miR‐155, miR‐21, miR‐221 and miR‐222) as well as those not previously reported in cancer (miR‐376a and miR‐301). Most of the top aberrantly expressed miRNAs displayed increased expression in the tumor. Expression of the active, mature microRNA was validated using a real‐time PCR assay to quantify the mature microRNA and Northern blotting. Reverse transcription in situ PCR showed that three of the top differentially expressed miRNAs (miR‐221, ‐376a and ‐301) were localized to tumor cells and not to stroma or normal acini or ducts. Aberrant microRNA expression may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma. © 2006 Wiley‐Liss, Inc.

[1]  A. Abioye,et al.  Pancreatic carcinoma. , 2020, Journal of the National Medical Association.

[2]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

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

[4]  J. Niederhuber,et al.  The national cancer data base report on pancreatic cancer , 1995, Cancer.

[5]  J. Herman,et al.  In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

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

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

[10]  Joshua M. Stuart,et al.  A Gene Expression Map for Caenorhabditis elegans , 2001, Science.

[11]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A I Saeed,et al.  TM4: a free, open-source system for microarray data management and analysis. , 2003, BioTechniques.

[13]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[14]  Christine A Iacobuzio-Donahue,et al.  Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. , 2003, The American journal of pathology.

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

[16]  R. Hruban,et al.  Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. , 2003, Cancer cell.

[17]  P. Sharp,et al.  Embryonic stem cell-specific MicroRNAs. , 2003, Developmental cell.

[18]  Rork Kuick,et al.  Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. , 2003, Cancer research.

[19]  O. Hobert.  Common logic of transcription factor and microRNA action. , 2004, Trends in biochemical sciences.

[20]  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.

[21]  R. Kuick,et al.  The Molecular Basis of Pancreatic Fibrosis: Common Stromal Gene Expression in Chronic Pancreatitis and Pancreatic Adenocarcinoma , 2004, Pancreas.

[22]  Sam Griffiths-Jones,et al.  The microRNA Registry , 2004, Nucleic Acids Res..

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

[24]  Qian Liu,et al.  A high-throughput method to monitor the expression of microRNA precursors. , 2004, Nucleic acids research.

[25]  N. Rajewsky,et al.  A pancreatic islet-specific microRNA regulates insulin secretion , 2004, Nature.

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

[27]  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.

[28]  C. Croce,et al.  The role of microRNA genes in papillary thyroid carcinoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[30]  Yuriy Gusev,et al.  Real-time expression profiling of microRNA precursors in human cancer cell lines , 2005, Nucleic acids research.

[31]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[32]  E. Miska,et al.  MicroRNA functions in animal development and human disease , 2005, Development.

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

[34]  C. Croce,et al.  MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  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.

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

[37]  A. Jemal,et al.  Cancer Statistics, 2005 , 2005, CA: a cancer journal for clinicians.

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

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

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

[41]  Kevin Kim,et al.  Targets of microRNA regulation in the Drosophila oocyte proteome. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Charles Auffray,et al.  Towards standardization of RNA quality assessment using user-independent classifiers of microcapillary electrophoresis traces , 2005, Nucleic acids research.

[43]  G. Maira,et al.  Extensive modulation of a set of microRNAs in primary glioblastoma. , 2005, Biochemical and biophysical research communications.

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

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

[46]  B. Tilton,et al.  Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues. , 2005, Molecular and cellular probes.

[47]  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.