title: Prognostic impact of bim, puma, and noxa expression in human colon carcinomas.
abstract: OBJECTIVE
  Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates.
  
  
  METHODS
  Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates.
  
  
  RESULTS
  Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011).
  
  
  CONCLUSIONS
  The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil-based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.
authors.affiliation: Division of Oncology, Mayo Clinic, Rochester, MN 55905, USA. sinicrope.frank@mayo.edu
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Rafaela L
authors.initials: RL
authors.lastname: Rego
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Harold E
authors.initials: HE
authors.lastname: Windschitl
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000032:analysis*; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005472:Fluorouracil
references.citation: Mol Cell. 2005 Feb 4;17(3):393-403
references.pmid: 15694340
references.citation: Science. 1993 May 7;260(5109):816-9
references.pmid: 8484122
references.citation: J Clin Oncol. 2004 May 1;22(9):1572-82
references.pmid: 15117979
references.citation: Science. 1997 Feb 14;275(5302):983-6
references.pmid: 9020082
references.citation: Blood. 2007 Jan 1;109(1):271-80
references.pmid: 16960149
references.citation: Blood. 2007 Jun 15;109(12):5430-8
references.pmid: 17332241
references.citation: Cell Death Differ. 2002 May;9(5):505-12
references.pmid: 11973609
references.citation: Oncogene. 2005 Feb 17;24(8):1348-58
references.pmid: 15608680
references.citation: J Exp Med. 2006 Dec 25;203(13):2939-51
references.pmid: 17178918
references.citation: Oncogene. 2002 May 13;21(21):3459-74
references.pmid: 12032782
references.citation: Cell Death Differ. 2003 Apr;10(4):451-60
references.pmid: 12719722
references.citation: J Natl Cancer Inst. 1999 Aug 4;91(15):1295-303
references.pmid: 10433618
references.citation: Cancer Res. 1998 Nov 15;58(22):5248-57
references.pmid: 9823339
references.citation: Cell Death Differ. 2006 Aug;13(8):1378-86
references.pmid: 16729025
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Immunity. 2003 Sep;19(3):341-52
references.pmid: 14499110
references.citation: Clin Colorectal Cancer. 2006 Jul;6(2):133-9
references.pmid: 16945169
references.citation: Cancer Res. 2001 Jan 1;61(1):333-8
references.pmid: 11196183
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9333-8
references.pmid: 15192153
references.citation: J Clin Oncol. 2002 Apr 1;20(7):1735-43
references.pmid: 11919229
references.citation: Apoptosis. 2007 Mar;12(3):613-22
references.pmid: 17216584
references.citation: Curr Biol. 2000 Oct 5;10(19):1201-4
references.pmid: 11050388
references.citation: Cancer Res. 2008 Apr 15;68(8):2944-51
references.pmid: 18413764
references.citation: Cancer Biol Ther. 2006 Apr;5(4):380-5
references.pmid: 16481741
references.citation: Oncogene. 2007 Feb 26;26(9):1324-37
references.pmid: 17322918
references.citation: Cancer Res. 2000 Apr 15;60(8):2225-31
references.pmid: 10786688
references.citation: Cancer. 2000 Apr 1;88(7):1739-57
references.pmid: 10738234
references.citation: Oncogene. 2005 Feb 3;24(6):1111-6
references.pmid: 15690057
references.citation: Science. 2007 Feb 9;315(5813):856-9
references.pmid: 17289999
references.citation: Science. 2000 May 12;288(5468):1053-8
references.pmid: 10807576
references.citation: Am J Gastroenterol. 2006 Dec;101(12):2818-25
references.pmid: 17026563
references.citation: Lancet. 2007 Dec 15;370(9604):2020-9
references.pmid: 18083404
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1931-6
references.pmid: 12574499
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Mol Cell. 2001 Mar;7(3):683-94
references.pmid: 11463392
references.citation: Science. 2003 Nov 7;302(5647):1036-8
references.pmid: 14500851
references.citation: Mol Cell. 2005 Feb 18;17(4):525-35
references.pmid: 15721256
references.citation: Clin Cancer Res. 1995 Oct;1(10):1103-10
references.pmid: 9815900
references.citation: Virchows Arch. 2003 Aug;443(2):115-21
references.pmid: 12802583
references.citation: Cancer Cell. 2003 Oct;4(4):321-8
references.pmid: 14585359
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9
references.pmid: 15079075
references.citation: Cancer Cell. 2005 Mar;7(3):227-38
references.pmid: 15766661
references.citation: CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
references.pmid: 17237035
references.citation: Cancer Res. 1993 Dec 15;53(24):5849-52
references.pmid: 8261392
references.citation: Mol Cancer Ther. 2005 Mar;4(3):443-9
references.pmid: 15767553
references.citation: Cancer Res. 1998 Apr 15;58(8):1713-8
references.pmid: 9563488