Targeting microRNAs in pancreatic cancer: microplayers in the big game.

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies result in only marginal survival rates for patients. The era of targeted therapies has offered a new avenue to search for more effective therapeutic strategies. Recently, microRNAs (miRNA) that are small noncoding RNAs (18-24 nucleotides) have been associated with a number of diseases, including cancer. Disruption of miRNAs may have important implications in cancer etiology, diagnosis, and treatment. So far, focus has been on the mechanisms that are involved in translational silencing of their targets to fine tune gene expression. This review summarizes the approach for rational validation of selected candidates that might be involved in pancreatic tumorigenesis, cancer progression, and disease management. Herein, we also focus on the major issues hindering the identification of miRNAs, their linked pathways and recent advances in understanding their role as diagnostic/prognostic biomarkers, and therapeutic tools in dealing with this disease. miRNAs are expected to be robust clinical analytes, valuable for clinical research and biomarker discovery.

[1]  D. V. Von Hoff,et al.  Phase I Trial of AEG35156 an Antisense Oligonucleotide to XIAP Plus Gemcitabine in Patients With Metastatic Pancreatic Ductal Adenocarcinoma , 2013, American journal of clinical oncology.

[2]  J. Long,et al.  MicroRNA-34b inhibits pancreatic cancer metastasis through repressing Smad3. , 2013, Current molecular medicine.

[3]  S. Kauppinen,et al.  Treatment of HCV infection by targeting microRNA. , 2013, The New England journal of medicine.

[4]  Shadan Ali,et al.  Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures. , 2013, Molecular nutrition & food research.

[5]  M. Gazouli,et al.  Expression of MicroRNAs in Patients With Pancreatic Cancer and Its Prognostic Significance , 2013, Pancreas.

[6]  M. Saif,et al.  Desmoplasia in Pancreatic Cancer. Can We Fight It? , 2012, Gastroenterology research and practice.

[7]  Lianyu Chen,et al.  miR‐301a promotes pancreatic cancer cell proliferation by directly inhibiting bim expression , 2012, Journal of cellular biochemistry.

[8]  P. Malfertheiner,et al.  Feasibility of Fecal MicroRNAs as Novel Biomarkers for Pancreatic Cancer , 2012, PloS one.

[9]  J. Long,et al.  microRNA signature for human pancreatic cancer invasion and metastasis. , 2012, Experimental and therapeutic medicine.

[10]  K. Ohuchida,et al.  MicroRNA-10a is Overexpressed in Human Pancreatic Cancer and Involved in Its Invasiveness Partially via Suppression of the HOXA1 Gene , 2012, Annals of Surgical Oncology.

[11]  Michael Goggins,et al.  MicroRNA Alterations of Pancreatic Intraepithelial Neoplasias , 2011, Clinical Cancer Research.

[12]  K. Ohuchida,et al.  MicroRNA-10b is overexpressed in pancreatic cancer, promotes its invasiveness, and correlates with a poor prognosis. , 2011, Surgery.

[13]  M. Friedrich-Rust,et al.  Serum MicroRNA-21 as Marker for Necroinflammation in Hepatitis C Patients with and without Hepatocellular Carcinoma , 2011, PloS one.

[14]  G. Calin,et al.  microRNA-10b: A New Marker or the Marker of Pancreatic Ductal Adenocarcinoma? , 2011, Clinical Cancer Research.

[15]  M. Korc,et al.  MicroRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma , 2011, Clinical Cancer Research.

[16]  Joshua T. Mendell,et al.  Restitution of Tumor Suppressor MicroRNAs Using a Systemic Nanovector Inhibits Pancreatic Cancer Growth in Mice , 2011, Molecular Cancer Therapeutics.

[17]  C. Croce,et al.  Abstract 139: MicroRNA-375 and microRNA-221: Potential noncoding RNAs associated with antiproliferative activity of benzyl isothiocyanate in pancreatic cancer , 2011 .

[18]  Yuriy Gusev,et al.  miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor. , 2011, Biochemical and biophysical research communications.

[19]  Zhongxin Lu,et al.  miR‐301a as an NF‐κB activator in pancreatic cancer cells , 2011, The EMBO journal.

[20]  Zhaohui Lu,et al.  miR-27a regulates the growth, colony formation and migration of pancreatic cancer cells by targeting Sprouty2. , 2010, Cancer letters.

[21]  K. Kelnar,et al.  Identification of miR-34a as a potent inhibitor of prostate cancer progenitor cells and metastasis by directly repressing CD44 , 2010, Nature Medicine.

[22]  Hua Zhang,et al.  Dysregulation of miR-15a and miR-214 in human pancreatic cancer , 2010, Journal of hematology & oncology.

[23]  Jia Yu,et al.  miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. , 2010, Cancer research.

[24]  M. Fournier,et al.  A need for basic research on fluid-based early detection biomarkers. , 2010, Cancer research.

[25]  G. Calin,et al.  Targeting MicroRNAs With Small Molecules: From Dream to Reality , 2010, Clinical pharmacology and therapeutics.

[26]  Yong-Tae Kim,et al.  Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer , 2010, PloS one.

[27]  R. Hruban,et al.  Aberrant MicroRNA-155 Expression Is an Early Event in the Multistep Progression of Pancreatic Adenocarcinoma , 2010, Pancreatology.

[28]  S. Kauppinen,et al.  Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection , 2010, Science.

[29]  Thomas D. Schmittgen,et al.  Antisense Inhibition of microRNA-21 or -221 Arrests Cell Cycle, Induces Apoptosis, and Sensitizes the Effects of Gemcitabine in Pancreatic Adenocarcinoma , 2009, Pancreas.

[30]  Min Zhang,et al.  MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells , 2009, PloS one.

[31]  Zhiwei Wang,et al.  Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. , 2009, Cancer research.

[32]  Norbert Senninger,et al.  Involvement of CD40 Targeting miR-224 and miR-486 on the Progression of Pancreatic Ductal Adenocarcinomas , 2009, Annals of Surgical Oncology.

[33]  K. Ohuchida,et al.  MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance , 2009, Molecular Cancer Therapeutics.

[34]  C. Croce,et al.  Regulation of microRNA expression by HMGA1 proteins , 2009, Oncogene.

[35]  Yanjie Lu,et al.  A single anti-microRNA antisense oligodeoxyribonucleotide (AMO) targeting multiple microRNAs offers an improved approach for microRNA interference , 2009, Nucleic acids research.

[36]  F. Huang,et al.  Effect of trichostatin a on viability and microRNA expression in human pancreatic cancer cell line BxPC-3. , 2008, Experimental oncology.

[37]  A. Rashid,et al.  MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers , 2008, Oncogene.

[38]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[39]  K. Coombes,et al.  Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells , 2008, Molecular Cancer Therapeutics.

[40]  Ladan Fazli,et al.  Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development , 2007, Proceedings of the National Academy of Sciences.

[41]  C. Croce,et al.  MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. , 2007, JAMA.

[42]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

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

[44]  Zhiguo Wang The concept of multiple-target anti-miRNA antisense oligonucleotide technology. , 2011, Methods in molecular biology.

[45]  I. Kim,et al.  Lin28-let7 modulates radiosensitivity of human cancer cells with activation of K-Ras. , 2010, International journal of radiation oncology, biology, physics.

[46]  H. Taubert,et al.  Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival , 2010, International journal of cancer.

[47]  Norbert Senninger,et al.  EP300—A miRNA‐regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas , 2010, International journal of cancer.

[48]  C. Esau,et al.  Inhibition of microRNA with antisense oligonucleotides. , 2008, Methods.