title: MicroRNA-130b promotes tumor development and is associated with poor prognosis in colorectal cancer.
abstract: MicroRNA-130b (miR-130b) is involved in several biologic processes; its role in colorectal tumorigenesis has not been addressed so far. Herein, we demonstrate that miR-130b up-regulation exhibits clinical relevance as it is linked to advanced colorectal cancers (CRCs), poor patients' prognosis, and molecular features of enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. miR-130b high-expressing cells develop large, dedifferentiated, and vascularized tumors in mouse xenografts, features that are reverted by intratumor injection of a specific antisense RNA. In contrast, injection of the corresponding mimic in mouse xenografts from miR-130b low-expressing cells increases tumor growth and angiogenic potential while reduces the epithelial hallmarks. These biologic effects are reproduced in human CRC cell lines. We identify peroxisome proliferator-activated receptor γ (PPARγ) as an miR-130b direct target in CRC in vitro and in vivo. Notably, the effects of PPARγ gain- and loss-of-function phenocopy those due to miR-130b down-regulation or up-regulation, respectively, underscoring their biologic relevance. Furthermore, we provide mechanistic evidences that most of the miR-130b-dependent effects are due to PPARγ suppression that in turn deregulates PTEN, E-cadherin, Snail, and vascular endothelial growth factor, key mediators of cell proliferation, EMT, and angiogenesis. Since higher levels of miR-130b are found in advanced tumor stages (III-IV), we propose a novel role of the miR-130b-PPARγ axis in fostering the progression toward more invasive CRCs. Detection of onco-miR-130b and its association with PPARγ may be useful as a prognostic biomarker. Its targeting in vivo should be evaluated as a novel effective therapeutic tool against CRC.
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Colangelo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fucci
authors.forename: Carolina
authors.initials: C
authors.lastname: Votino
authors.forename: Lina
authors.initials: L
authors.lastname: Sabatino
authors.forename: Massimo
authors.initials: M
authors.lastname: Pancione
authors.forename: Carmelo
authors.initials: C
authors.lastname: Laudanna
authors.forename: Monica
authors.initials: M
authors.lastname: Binaschi
authors.forename: Mario
authors.initials: M
authors.lastname: Bigioni
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
authors.forename: Domenico
authors.initials: D
authors.lastname: Parente
authors.forename: Nicola
authors.initials: N
authors.lastname: Forte
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011379:Prognosis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; D047495:PPAR gamma; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references.citation: ACS Chem Biol. 2011 May 20;6(5):452-65
references.pmid: 21241068
references.citation: Neoplasia. 2010 Mar;12(3):224-34
references.pmid: 20234816
references.citation: Oncogene. 2012 Apr 19;31(16):2062-74
references.pmid: 21874049
references.citation: Cancer Res. 2008 May 15;68(10):3645-54
references.pmid: 18483246
references.citation: Clin Cancer Res. 2012 Jun 1;18(11):3054-70
references.pmid: 22452939
references.citation: Annu Rev Cell Dev Biol. 2011;27:347-76
references.pmid: 21740232
references.citation: Mol Cell Biol. 2006 Oct;26(20):7561-74
references.pmid: 17015477
references.citation: Br J Cancer. 2010 May 25;102(11):1555-77
references.pmid: 20502460
references.citation: Cancer Res. 1998 Dec 15;58(24):5633-6
references.pmid: 9865711
references.citation: Nat Immunol. 2008 Aug;9(8):839-45
references.pmid: 18645592
references.citation: Cancer Biol Ther. 2005 Jul;4(7):687-93
references.pmid: 16082179
references.citation: J Surg Oncol. 2013 Apr;107(5):505-10
references.pmid: 22996433
references.citation: PLoS One. 2010 Dec 03;5(12):e14229
references.pmid: 21151932
references.citation: Br J Cancer. 2012 Jul 10;107(2):352-9
references.pmid: 22677902
references.citation: Mol Cell Biochem. 2011 Dec;358(1-2):375-85
references.pmid: 21769449
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W478-83
references.pmid: 22573175
references.citation: Med Oncol. 2013 Mar;30(1):484
references.pmid: 23392577
references.citation: Carcinogenesis. 2010 Sep;31(9):1567-75
references.pmid: 20631058
references.citation: Clin Ther. 2010 Mar;32(3):437-53
references.pmid: 20399983
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):219-30
references.pmid: 18270516
references.citation: Genes Dev. 2005 Aug 1;19(15):1737-42
references.pmid: 16077002
references.citation: PLoS One. 2012;7(5):e35661
references.pmid: 22623952
references.citation: PPAR Res. 2008;2008:932632
references.pmid: 19096712
references.citation: J Surg Oncol. 2013 Feb;107(2):148-54
references.pmid: 22926658
references.citation: Mol Cell. 1998 Feb;1(3):465-70
references.pmid: 9660931
references.citation: Cancer Epidemiol Biomarkers Prev. 1997 Feb;6(2):131-5
references.pmid: 9037564
references.citation: Hum Pathol. 2013 Feb;44(2):173-80
references.pmid: 22974478
references.citation: Oncogene. 2013 Jul 4;32(27):3286-95
references.pmid: 22847613
references.citation: Stat Appl Genet Mol Biol. 2003;2:Article1
references.pmid: 16646779
references.citation: Cancer Discov. 2012 Jun;2(6):540-53
references.pmid: 22628407
references.citation: Biochem Biophys Res Commun. 2009 Dec 11;390(2):247-51
references.pmid: 19800867
references.citation: Nat Rev Cancer. 2004 Jan;4(1):61-70
references.pmid: 14708026
references.citation: N Engl J Med. 2012 Jun 21;366(25):2345-57
references.pmid: 22612596
references.citation: Mol Cancer Res. 2012 Apr;10(4):504-15
references.pmid: 22343615
references.citation: Gastroenterology. 2009 Apr;136(4):1242-50
references.pmid: 19186181
references.citation: World J Gastroenterol. 2012 Feb 21;18(7):601-8
references.pmid: 22363130
references.citation: Annu Rev Med. 2009;60:167-79
references.pmid: 19630570
references.citation: J Oncol. 2012;2012:141236
references.pmid: 21904550
references.citation: Clin Cancer Res. 2004 Mar 15;10(6):1911-9
references.pmid: 15041706
references.citation: Eur J Cancer. 2010 May;46(8):1456-63
references.pmid: 20176475
references.citation: Nucleic Acids Res. 2011 Aug;39(14):6086-99
references.pmid: 21486751
references.citation: Mol Cell Biol. 2011 Feb;31(4):626-38
references.pmid: 21135128
references.citation: Genes Dev. 2005 Feb 1;19(3):362-75
references.pmid: 15687259
references.citation: Cell. 2010 Jun 25;141(7):1195-207
references.pmid: 20603000
references.citation: BMJ Open. 2012 Mar 08;2(2):e000825
references.pmid: 22403344
references.citation: Oncogene. 2012 Dec 6;31(49):5061-72
references.pmid: 22286757
references.citation: Hum Pathol. 2009 May;40(5):714-25
references.pmid: 19121846