title: MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes.
abstract: Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-κB transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF-κB-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies.
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.|The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Keklikoglou
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Hosaka
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bender
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bott
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Koerner
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Mitra
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Will
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Woerner
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Muenstermann
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Wilhelm
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.|Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.|Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wiemann
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017306:Annexin A2 / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; C117307:KRAS protein, human; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins