title: Pro-tumorigenic effects of miR-31 loss in mesothelioma.
abstract: The human genome encodes several hundred microRNA (miRNA) genes that produce small (21-23n) single strand regulatory RNA molecules. Although abnormal expression of miRNAs has been linked to cancer progression, the mechanisms of this dysregulation are poorly understood. Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal cancer resistant to conventional therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a microRNA recently linked with suppression of breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival phosphatase PPP6C, which was previously associated with chemotherapy and radiation therapy resistance, and maintenance of chromosomal stability. PPP6C, whose mRNA is distinguished with three miR-31-binding sites in its 3'-untranslated region, was consistently down-regulated by miR-31 introduction and up-regulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that tumor-suppressive propensity of miR-31 can be used for development of new therapies against mesothelioma and other cancers that show loss of the 9p21.3 chromosome.
authors.affiliation: Department of Otolaryngology, Vanderbilt School of Medicine, Nashville, Tennessee 37232, USA. sergey.v.ivanov@vanderbilt.edu
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ivanov
authors.forename: Chandra M V
authors.initials: CM
authors.lastname: Goparaju
authors.forename: Peter
authors.initials: P
authors.lastname: Lopez
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Ginat
authors.initials: G
authors.lastname: Toren-Haritan
authors.forename: Shai
authors.initials: S
authors.lastname: Rosenwald
authors.forename: Moshe
authors.initials: M
authors.lastname: Hoshen
authors.forename: Ayelet
authors.initials: A
authors.lastname: Chajut
authors.forename: Dalia
authors.initials: D
authors.lastname: Cohen
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
mesh_terms: D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008654:Mesothelioma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D015203:Reproducibility of Results; D016615:Telomere / Q000235:genetics
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6
references.citation: Br J Cancer. 2008 Jul 22;99(2):364-70
references.pmid: 18612309
references.citation: Plant Methods. 2007 Oct 12;3:12
references.pmid: 17931426
references.citation: Int J Cancer. 2009 Feb 1;124(3):589-99
references.pmid: 18973227
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: Nat Cell Biol. 2005 Jun;7(6):591-600
references.pmid: 15864305
references.citation: Genome Biol. 2007;8(1):R3
references.pmid: 17204154
references.citation: Oncol Res. 2004;14(7-8):373-9
references.pmid: 15301428
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W317-22
references.pmid: 19465387
references.citation: Cell. 2009 Jun 12;137(6):1032-46
references.pmid: 19524507
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2602-11
references.pmid: 19351750
references.citation: Cancer Res. 1994 Nov 1;54(21):5547-51
references.pmid: 7923195
references.citation: J Pathol. 1999 Mar;187(4):403-9
references.pmid: 10398098
references.citation: Biochim Biophys Acta. 1998 Oct 14;1378(2):F115-77
references.pmid: 9823374
references.citation: Mol Cell Biol. 2000 Feb;20(4):1436-47
references.pmid: 10648628
references.citation: Nat Genet. 1994 Sep;8(1):27-32
references.pmid: 7726912
references.citation: Nature. 2007 Aug 23;448(7156):943-6
references.pmid: 17713536
references.citation: J Urol. 2003 Aug;170(2 Pt 1):595-600
references.pmid: 12853838
references.citation: J Cell Physiol. 1999 Aug;180(2):150-7
references.pmid: 10395284
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004
references.pmid: 14973191
references.citation: J Invest Dermatol. 2009 May;129(5):1149-55
references.pmid: 19020554
references.citation: Mutat Res. 2005 Aug 25;576(1-2):22-38
references.pmid: 15878778
references.citation: Virchows Arch. 2008 Dec;453(6):627-35
references.pmid: 18958493
references.citation: Clin Cancer Res. 2002 Mar;8(3):782-7
references.pmid: 11895909
references.citation: Int J Cancer. 2009 May 1;124(9):2236-42
references.pmid: 19127597
references.citation: Clin Cancer Res. 2005 Apr 15;11(8):2991-7
references.pmid: 15837753
references.citation: Bioinformatics. 2005 Mar;21(6):821-2
references.pmid: 15531610
references.citation: Mol Cancer Ther. 2005 Dec;4(12):1860-6
references.pmid: 16373701
references.citation: J Cell Sci. 1996 Dec;109 ( Pt 12):2865-74
references.pmid: 9013334
references.citation: Cancer Res. 1993 Mar 1;53(5):1098-101
references.pmid: 8382555
references.citation: Nucleic Acids Res. 2005 Nov 27;33(20):e179
references.pmid: 16314309
references.citation: EMBO J. 2003 Jun 2;22(11):2752-63
references.pmid: 12773390
references.citation: PLoS One. 2009;4(2):e4395
references.pmid: 19198648
references.citation: Nat Biotechnol. 2008 Apr;26(4):462-9
references.pmid: 18362881
references.citation: J Clin Invest. 2007 Aug;117(8):2059-66
references.pmid: 17671640
references.citation: Cell. 2006 Oct 20;127(2):265-75
references.pmid: 17055429
references.citation: Cancer Res. 2010 Mar 1;70(5):1916-24
references.pmid: 20160038
references.citation: Nucleic Acids Res. 2008 Sep;36(16):5391-404
references.pmid: 18701644
references.citation: Med Oncol. 2010 Sep;27(3):685-9
references.pmid: 19598010
references.citation: N Engl J Med. 2008 Jan 31;358(5):502-11
references.pmid: 18234754
references.citation: Annu Rev Med. 2009;60:167-79
references.pmid: 19630570
references.citation: Leuk Res. 2008 Aug;32(8):1228-35
references.pmid: 18328560
references.citation: Future Oncol. 2005 Feb;1(1):79-92
references.pmid: 16555978
references.citation: Cancer Res. 2009 Jul 1;69(13):5467-74
references.pmid: 19549896
references.citation: Cancer Res. 1991 Jun 15;51(12):3193-7
references.pmid: 1904005
references.citation: Brain Pathol. 2000 Jul;10(3):395-401
references.pmid: 10885658
references.citation: Ann Thorac Surg. 1995 Apr;59(4):835-44
references.pmid: 7695406
references.citation: Cell. 2006 Sep 22;126(6):1203-17
references.pmid: 16990141