A six-microRNA set as prognostic indicators for bile duct cancer.

MicroRNAs (miRNAs) play important roles in cancer progression by altering transcriptional control. The purpose of this study is to identify and explore specific miRNAs as prognostic and predictive biomarkers for bile duct cancer (BDC) by analyzing Next-generation data. miRNA expression profiles and corresponding clinical information of BDC samples were extracted from The Cancer Genome Atlas (TCGA). The differentially expressed miRNAs were determined by SAMR package in R software. Target genes of those miRNAs were predicted by Targetscan. Functional enrichment analysis and hypergeometric test analysis of target genes were performed. Then, diagnosis accuracy of miRNAs was judged by ROC Curves analysis. Total 120 differentially expressed miRNAs were obtained, of which six important miRNAs were selected and predicted as prognosis and predicting biomarkers in BDC. Besides, functional analysis showed that both enriched pathways were significantly related with ion binding, which might involve in the carcinogenesis of BDC. Moreover, top 3 important pathways sharing the most influence were noted. Our results demonstrated that hsa-miR-483-5p, hsa-miR-675, hsa-miR-139-3p, hsa-miR-598, hsa-miR-625 and hsa-miR-187 could serve as prognostic and predictive markers for survival of BDC patients and could potentially be provided as targets for future therapy.

[1]  Le Yu,et al.  The role of microRNA expression pattern in human intrahepatic cholangiocarcinoma. , 2009, Journal of hepatology.

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

[3]  H. Swerdlow,et al.  A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers , 2012, BMC Genomics.

[4]  Yanchun Deng,et al.  MiR‐483–5p suppresses the proliferation of glioma cells via directly targeting ERK1 , 2012, FEBS letters.

[5]  Anindya Dutta,et al.  The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. , 2007, Genes & development.

[6]  A. Kulkarni,et al.  Current research in perineural invasion of cholangiocarcinoma , 2010, Journal of experimental & clinical cancer research : CR.

[7]  H. Thomas,et al.  Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update , 2012, Gut.

[8]  Andrey Golubov,et al.  Alterations of microRNAs and their targets are associated with acquired resistance of MCF‐7 breast cancer cells to cisplatin , 2010, International journal of cancer.

[9]  S. DeMorrow,et al.  Genetic and epigenetic changes associated with cholangiocarcinoma: from DNA methylation to microRNAs. , 2007, World journal of gastroenterology.

[10]  S. Thorgeirsson,et al.  Genetic profiling of intrahepatic cholangiocarcinoma , 2012, Current opinion in gastroenterology.

[11]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[12]  Chi-Ying F. Huang,et al.  miRTarBase: a database curates experimentally validated microRNA–target interactions , 2010, Nucleic Acids Res..

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

[14]  Mahlon D. Johnson,et al.  Increased STAT-3 and synchronous activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas , 2008, Journal of Neuro-Oncology.

[15]  T. Patel,et al.  The MicroRNA let-7a Modulates Interleukin-6-dependent STAT-3 Survival Signaling in Malignant Human Cholangiocytes* , 2007, Journal of Biological Chemistry.

[16]  J. Marin,et al.  MicroRNAs in biliary diseases. , 2012, World journal of gastroenterology.

[17]  Levi Garraway,et al.  High‐throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide‐3‐kinase and other oncogenes , 2012, Cancer.

[18]  Anthony J Gill,et al.  miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer , 2009, Clinical Cancer Research.

[19]  William C Reinhold,et al.  MicroRNAs modulate the chemosensitivity of tumor cells , 2008, Molecular Cancer Therapeutics.

[20]  C. Corless,et al.  Protein kinase A RII-like (R2D2) proteins exhibit differential localization and AKAP interaction. , 2008, Cell motility and the cytoskeleton.

[21]  L. Mazzucchelli.  Protein S100A4: too long overlooked by pathologists? , 2002, The American journal of pathology.

[22]  Jaakko Astola,et al.  Comparison of Affymetrix data normalization methods using 6,926 experiments across five array generations , 2009, BMC Bioinformatics.

[23]  T. Okanoue,et al.  Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues , 2006, Oncogene.

[24]  Shuomin Zhu,et al.  MicroRNA-21 targets tumor suppressor genes in invasion and metastasis , 2008, Cell Research.

[25]  G. Gores,et al.  mir-29 regulates Mcl-1 protein expression and apoptosis , 2007, Oncogene.

[26]  V. Ambros,et al.  MicroRNA Pathways in Flies and Worms Growth, Death, Fat, Stress, and Timing , 2003, Cell.

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

[28]  J M Bland,et al.  Statistical methods for assessing agreement between two methods of clinical measurement , 1986 .

[29]  H. El‐Serag,et al.  The epidemiology of cholangiocarcinoma. , 2004, Seminars in liver disease.

[30]  G. Gores,et al.  MicroRNA‐21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3 , 2009, Hepatology.

[31]  I. Ng,et al.  The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. , 2011, Gastroenterology.

[32]  Chuan-hai Zhang,et al.  MicroRNA-21 regulates the invasion and metastasis in cholangiocarcinoma and may be a potential biomarker for cancer prognosis. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[33]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[34]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.