title: IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling.
abstract: Osteosarcoma is a common malignant bone tumor with a propensity to metastasize to the lungs. Epigenetic abnormalities have been demonstrated to underlie osteosarcoma development; however, the epigenetic mechanisms that are involved in metastasis are not yet clear. Here, we analyzed 2 syngeneic primary human osteosarcoma cell lines that exhibit disparate metastatic potential for differences in epigenetic modifications and expression. Using methylated DNA immunoprecipitation (MeDIP) and microarray expression analysis to screen for metastasis-associated genes, we identified Iroquois homeobox 1 (IRX1). In both human osteosarcoma cell lines and clinical osteosarcoma tissues, IRX1 overexpression was strongly associated with hypomethylation of its own promoter. Furthermore, experimental modulation of IRX1 in osteosarcoma cell lines profoundly altered metastatic activity, including migration, invasion, and resistance to anoikis in vitro, and influenced lung metastasis in murine models. These prometastatic effects of IRX1 were mediated by upregulation of CXCL14/NF-κB signaling. In serum from osteosarcoma patients, the presence of IRX1 hypomethylation in circulating tumor DNA reduced lung metastasis-free survival. Together, these results identify IRX1 as a prometastatic gene, implicate IRX1 hypomethylation as a potential molecular marker for lung metastasis, and suggest that epigenetic reversion of IRX1 activation may be beneficial for controlling osteosarcoma metastasis.
authors.forename: Jinchang
authors.initials: J
authors.lastname: Lu
authors.forename: Guohui
authors.initials: G
authors.lastname: Song
authors.forename: Qinglian
authors.initials: Q
authors.lastname: Tang
authors.forename: Changye
authors.initials: C
authors.lastname: Zou
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Bicheng
authors.initials: B
authors.lastname: Yong
authors.forename: Junqiang
authors.initials: J
authors.lastname: Yin
authors.forename: Huaiyuan
authors.initials: H
authors.lastname: Xu
authors.forename: Xianbiao
authors.initials: X
authors.lastname: Xie
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.forename: YingLee
authors.initials: Y
authors.lastname: Lam
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.forename: Jingnan
authors.initials: J
authors.lastname: Shen
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D023102:Anoikis; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D019743:Chemokines, CXC / Q000502:physiology*; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D057166:High-Throughput Screening Assays; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D018398:Homeodomain Proteins; C501591:IRX1 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors
references.citation: J Pathol. 2012 Jan;226(2):148-57
references.pmid: 21989643
references.citation: Apoptosis. 2013 Aug;18(8):949-62
references.pmid: 23588592
references.citation: Expert Rev Anticancer Ther. 2008 Aug;8(8):1257-69
references.pmid: 18699764
references.citation: Cancer Res. 2006 Sep 15;66(18):9202-10
references.pmid: 16982764
references.citation: Int J Cell Biol. 2012;2012:306879
references.pmid: 22505926
references.citation: Nat Rev Cancer. 2011 Jun;11(6):426-37
references.pmid: 21562580
references.citation: Mech Dev. 2001 Aug;106(1-2):159-62
references.pmid: 11472848
references.citation: BMC Musculoskelet Disord. 2004 Feb 26;5:6
references.pmid: 15102339
references.citation: Nan Fang Yi Ke Da Xue Xue Bao. 2013 Jun;33(6):798-803
references.pmid: 23803187
references.citation: Oncogene. 2011 Sep 15;30(37):3907-17
references.pmid: 21460855
references.citation: Acta Pharmacol Sin. 2008 Mar;29(3):325-32
references.pmid: 18298897
references.citation: Cancer Res. 2009 Mar 15;69(6):2375-83
references.pmid: 19276362
references.citation: Mol Cell Biol. 2008 Dec;28(23):7168-81
references.pmid: 18809576
references.citation: Development. 2001 Aug;128(15):2847-55
references.pmid: 11532909
references.citation: Surg Today. 2006;36(9):793-801
references.pmid: 16937283
references.citation: Oncogene. 2002 Aug 12;21(35):5400-13
references.pmid: 12154403
references.citation: Nat Rev Genet. 2007 May;8(5):341-52
references.pmid: 17440531
references.citation: J Biol Chem. 2003 Aug 8;278(32):29676-85
references.pmid: 12777377
references.citation: Clin Exp Metastasis. 2005;22(4):319-29
references.pmid: 16170668
references.citation: Nat Neurosci. 2004 Jun;7(6):605-12
references.pmid: 15133517
references.citation: Biochem Biophys Res Commun. 2012 Mar 23;419(4):801-8
references.pmid: 22390931
references.citation: Hepatology. 2007 May;45(5):1306-12
references.pmid: 17464973
references.citation: Cancer Lett. 2011 Dec 1;311(1):113-21
references.pmid: 21835542
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: Cancer Lett. 2014 Jan 1;342(1):150-8
references.pmid: 24012639
references.citation: Cancer Genet Cytogenet. 2007 Nov;179(1):52-61
references.pmid: 17981215
references.citation: Mol Cell Biol. 2001 Aug;21(16):5299-305
references.pmid: 11463813
references.citation: Am J Pathol. 2000 Jun;156(6):1937-50
references.pmid: 10854217
references.citation: Nat Rev Cancer. 2002 Mar;2(3):210-9
references.pmid: 11990857
references.citation: Annu Rev Med. 2012;63:199-215
references.pmid: 22053740
references.citation: Biochem Biophys Res Commun. 1999 Feb 24;255(3):703-6
references.pmid: 10049774
references.citation: Ann Surg. 2001 Jul;234(1):10-20
references.pmid: 11420478
references.citation: Cell. 2006 Nov 17;127(4):679-95
references.pmid: 17110329
references.citation: Biochem Biophys Res Commun. 2006 Sep 22;348(2):406-12
references.pmid: 16884687
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3562-70
references.pmid: 18519790
references.citation: Prostate. 2005 Jun 15;64(1):67-74
references.pmid: 15651028
references.citation: Microbiol Rev. 1991 Sep;55(3):451-8
references.pmid: 1943996
references.citation: J Biol Chem. 2004 Jul 23;279(30):31735-44
references.pmid: 15150277
references.citation: Ann N Y Acad Sci. 2004 Jun;1022:44-9
references.pmid: 15251938
references.citation: Am J Clin Nutr. 2002 Nov;76(5):1172S-6S
references.pmid: 12418499
references.citation: Nature. 2004 May 27;429(6990):457-63
references.pmid: 15164071
references.citation: J Transl Med. 2013;11:6
references.pmid: 23294544
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14671-6
references.pmid: 16203991
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4735-42
references.pmid: 18676742
references.citation: Am J Med Genet A. 2006 May 15;140(10):1059-68
references.pmid: 16596674
references.citation: Exp Oncol. 2012 Oct;34(3):176-84
references.pmid: 23070002
references.citation: Wiley Interdiscip Rev Syst Biol Med. 2009 Jul-Aug;1(1):107-15
references.pmid: 20151024
references.citation: Cancer Cell Int. 2007 Sep 10;7:14
references.pmid: 17845729
references.citation: Cancer Lett. 2008 Dec 18;272(2):177-85
references.pmid: 18579285
references.citation: Genes Chromosomes Cancer. 2006 Sep;45(9):829-38
references.pmid: 16752383
references.citation: J Natl Cancer Inst. 2012 May 16;104(10):749-63
references.pmid: 22534782
references.citation: Science. 1980 Nov 7;210(4470):604-10
references.pmid: 6254144
references.citation: Cancer Lett. 2008 Feb 8;259(2):209-17
references.pmid: 18054154
references.citation: Development. 2002 May;129(10):2317-27
references.pmid: 11973265
references.citation: Prostate. 2007 Nov 1;67(15):1621-9
references.pmid: 17823924
references.citation: Nat Rev Cancer. 2004 Jul;4(7):540-50
references.pmid: 15229479
references.citation: J Biol Chem. 1997 Aug 22;272(34):21096-103
references.pmid: 9261113
references.citation: Hum Mol Genet. 2012 May 1;21(9):2076-85
references.pmid: 22323358
references.citation: J Biol Chem. 2003 Jun 6;278(23):20812-20
references.pmid: 12676953
references.citation: Clin Exp Metastasis. 2009;26(1):5-18
references.pmid: 18386135
references.citation: Oncogene. 2010 Jul 8;29(27):3908-20
references.pmid: 20440264
references.citation: Epigenomics. 2009 Dec;1(2):239-59
references.pmid: 20495664
references.citation: Cancer Metastasis Rev. 2010 Dec;29(4):709-22
references.pmid: 20839032
references.citation: Cancer Res. 2008 Jun 15;68(12):4494-9
references.pmid: 18559491
references.citation: Clin Exp Metastasis. 2009;26(7):599-610
references.pmid: 19363654
references.citation: Neoplasia. 2008 May;10(5):471-80
references.pmid: 18472964
references.citation: Cancer Cell. 2004 Jul;6(1):17-32
references.pmid: 15261139
references.citation: Nat Rev Cancer. 2003 Apr;3(4):253-66
references.pmid: 12671664
references.citation: Genes Cancer. 2011 Jun;2(6):648-62
references.pmid: 21941620