title: Molecular profiling of multiple human cancers defines an inflammatory cancer-associated molecular pattern and uncovers KPNA2 as a uniform poor prognostic cancer marker.
abstract: BACKGROUND
  Immune evasion is one of the recognized hallmarks of cancer. Inflammatory responses to cancer can also contribute directly to oncogenesis. Since the immune system is hardwired to protect the host, there is a possibility that cancers, regardless of their histological origins, endow themselves with a common and shared inflammatory cancer-associated molecular pattern (iCAMP) to promote oncoinflammation. However, the definition of iCAMP has not been conceptually and experimentally investigated.
  
  
  RESULTS
  Genome-wide cDNA expression data was analyzed for 221 normal and 324 cancer specimens from 7 cancer types: breast, prostate, lung, colon, gastric, oral and pancreatic. A total of 96 inflammatory genes with consistent dysregulation were identified, including 44 up-regulated and 52 down-regulated genes. Protein expression was confirmed by immunohistochemistry for some of these genes. The iCAMP contains proteins whose roles in cancer have been implicated and others which are yet to be appreciated. The clinical significance of many iCAMP genes was confirmed in multiple independent cohorts of colon and ovarian cancer patients. In both cases, better prognosis correlated strongly with high CXCL13 and low level of GREM1, LOX, TNFAIP6, CD36, and EDNRA. An "Inflammatory Gene Integrated Score" was further developed from the combination of 18 iCAMP genes in ovarian cancer, which predicted overall survival. Noticeably, as a selective nuclear import protein whose immuno-regulatory function just begins to emerge, karyopherin alpha 2 (KPNA2) is uniformly up-regulated across cancer types. For the first time, the cancer-specific up-regulation of KPNA2 and its clinical significance were verified by tissue microarray analysis in colon and head-neck cancers.
  
  
  CONCLUSIONS
  This work defines an inflammatory signature shared by seven epithelial cancer types and KPNA2 as a consistently up-regulated protein in cancer. Identification of iCAMP may not only serve as a novel biomarker for prognostication and individualized treatment of cancer, but also have significant biological implications.
authors.affiliation: Department of Microbiology and Immunology, South Carolina Clinical and Translational Research Institute (SCTR), Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Rachidi
authors.forename: Tingting
authors.initials: T
authors.lastname: Qin
authors.forename: Shaoli
authors.initials: S
authors.lastname: Sun
authors.forename: W Jim
authors.initials: WJ
authors.lastname: Zheng
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000401:mortality; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000401:mortality; D015815:Cell Adhesion Molecules / Q000235:genetics; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000401:mortality; D057225:Data Mining; D030541:Databases, Genetic; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000401:mortality; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000276:immunology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications* / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck; D057188:Workflow; D028901:alpha Karyopherins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C072273:TNFAIP6 protein, human; D028901:alpha Karyopherins; C087978:karyopherin alpha 2
references.citation: Br J Cancer. 2004 Feb 9;90(3):686-92
references.pmid: 14760385
references.citation: J Clin Oncol. 2008 Feb 10;26(5):729-35
references.pmid: 18258980
references.citation: Eur J Cancer. 2009 Feb;45(3):461-9
references.pmid: 19081245
references.citation: PLoS One. 2010 Apr 22;5(4):e10312
references.pmid: 20421987
references.citation: Dev Cell. 2008 Jun;14(6):818-29
references.pmid: 18539112
references.citation: Int J Oncol. 2011 Aug;39(2):337-44
references.pmid: 21617854
references.citation: Bioinformatics. 2006 Nov 15;22(22):2825-7
references.pmid: 16982708
references.citation: Am J Pathol. 1994 Sep;145(3):610-23
references.pmid: 8080043
references.citation: Cell Immunol. 2010;261(2):128-33
references.pmid: 20038463
references.citation: Stat Med. 2009 Nov 10;28(25):3049-67
references.pmid: 19630097
references.citation: Cancer Res. 2007 Jul 1;67(13):6163-73
references.pmid: 17616673
references.citation: J Biomed Sci. 2005;12(1):65-77
references.pmid: 15864740
references.citation: Gastroenterology. 2010 Apr;138(4):1429-40
references.pmid: 19909745
references.citation: Science. 2011 Mar 25;331(6024):1565-70
references.pmid: 21436444
references.citation: N Engl J Med. 2004 Dec 30;351(27):2817-26
references.pmid: 15591335
references.citation: J Neurooncol. 2012 Sep;109(3):545-53
references.pmid: 22772608
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Cancer Res. 2008 Jul 1;68(13):5478-86
references.pmid: 18593951
references.citation: Dis Esophagus. 2009;22(1):49-54
references.pmid: 18564160
references.citation: J Natl Cancer Inst. 2006 Apr 5;98(7):472-82
references.pmid: 16595783
references.citation: BMC Bioinformatics. 2011 Nov 11;12:438
references.pmid: 22078224
references.citation: Anticancer Res. 2010 Mar;30(3):851-6
references.pmid: 20393006
references.citation: Mod Pathol. 2011 Mar;24(3):463-70
references.pmid: 21102419
references.citation: Cancer Cell. 2009 Jan 6;15(1):35-44
references.pmid: 19111879
references.citation: Adv Immunol. 2007;94:245-73
references.pmid: 17560277
references.citation: J Transl Med. 2012 Oct 03;10:205
references.pmid: 23034130
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: J Hematol Oncol. 2009 Jan 30;2:5
references.pmid: 19183457
references.citation: EMBO J. 2008 Jun 18;27(12):1671-81
references.pmid: 18511911
references.citation: Eur J Gastroenterol Hepatol. 2007 Sep;19(9):775-82
references.pmid: 17700263
references.citation: Cytokine Growth Factor Rev. 1997 Jun;8(2):143-56
references.pmid: 9244409
references.citation: Cancer Lett. 2010 Mar 28;289(2):170-7
references.pmid: 19733004
references.citation: Int J Cancer. 2010 Mar 1;126(5):1177-86
references.pmid: 19795455
references.citation: PLoS One. 2012;7(9):e42992
references.pmid: 22962582
references.citation: Annu Rev Immunol. 2005;23:337-66
references.pmid: 15771574
references.citation: BMC Cancer. 2007 Mar 27;7:55
references.pmid: 17389037
references.citation: Oncogene. 2012 Apr 19;31(16):2101-14
references.pmid: 21909132
references.citation: Int J Cancer. 2011 May 15;128(10):2364-72
references.pmid: 20658535
references.citation: Nature. 2011 Jul 13;475(7355):226-30
references.pmid: 21753853
references.citation: Biol Reprod. 2011 Dec;85(6):1191-202
references.pmid: 21900684
references.citation: Clin Cancer Res. 2004 May 15;10(10):3291-300
references.pmid: 15161682
references.citation: Virchows Arch. 2007 Nov;451(5):877-81
references.pmid: 17899179
references.citation: PLoS One. 2010 Oct 01;5(10):
references.pmid: 20957034
references.citation: Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:1-13
references.pmid: 2700931
references.citation: Genome Biol. 2007;8(7):R131
references.pmid: 17615082
references.citation: Cancer Sci. 2009 May;100(5):873-80
references.pmid: 19445022
references.citation: J Genet Genomics. 2008 Dec;35(12):723-8
references.pmid: 19103427
references.citation: Hepatogastroenterology. 2008 Nov-Dec;55(88):2016-27
references.pmid: 19260470
references.citation: BMC Genomics. 2008 Feb 06;9:69
references.pmid: 18254958
references.citation: J Invest Dermatol. 2007 Jun;127(6):1456-64
references.pmid: 17255955
references.citation: J Immunol. 2010 Dec 15;185(12):7443-51
references.pmid: 21068403
references.citation: Int J Cancer. 2007 Nov 1;121(9):2005-12
references.pmid: 17640062
references.citation: Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6532-6
references.pmid: 7604027
references.citation: FASEB J. 2011 Nov;25(11):3958-65
references.pmid: 21840941
references.citation: Clin Cancer Res. 2004 Nov 1;10(21):7252-9
references.pmid: 15534099
references.citation: J Natl Cancer Inst. 2011 Nov 16;103(22):1696-712
references.pmid: 22025622
references.citation: Nat Rev Immunol. 2006 Apr;6(4):295-307
references.pmid: 16557261
references.citation: Clin Cancer Res. 2011 Mar 1;17(5):1111-21
references.pmid: 21220479
references.citation: Mol Cancer Res. 2009 Feb;7(2):199-209
references.pmid: 19208741
references.citation: Cancer Res. 2002 Aug 15;62(16):4722-9
references.pmid: 12183431
references.citation: Eur Respir J. 2012 May;39(5):1171-80
references.pmid: 21965228
references.citation: Infect Immun. 2004 Dec;72(12):6987-93
references.pmid: 15557621
references.citation: Int J Cancer. 2009 Oct 1;125(7):1626-39
references.pmid: 19569244
references.citation: Cancer Res. 2010 Aug 15;70(16):6448-55
references.pmid: 20663908
references.citation: Cytokine Growth Factor Rev. 2010 Feb;21(1):11-9
references.pmid: 20018552
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1176-81
references.pmid: 11158614
references.citation: Cell. 2010 Mar 19;140(6):883-99
references.pmid: 20303878
references.citation: J Clin Oncol. 2005 Oct 10;23(29):7257-64
references.pmid: 16087957
references.citation: Clin Cancer Res. 2008 Aug 15;14(16):5198-208
references.pmid: 18698038
references.citation: Ann Oncol. 2007 Feb;18(2):269-74
references.pmid: 17065588
references.citation: Eur Urol. 2011 May;59(5):841-8
references.pmid: 21330047
references.citation: Obstet Gynecol. 2010 Oct;116(4):884-891
references.pmid: 20859152
references.citation: Gastroenterology. 2010 Mar;138(3):958-68
references.pmid: 19914252
references.citation: J Virol. 2007 Sep;81(18):9812-24
references.pmid: 17596301
references.citation: Cancer Res. 2006 Feb 1;66(3):1354-62
references.pmid: 16452189
references.citation: Mol Biol Cell. 2003 Nov;14(11):4376-86
references.pmid: 12960427