title: Downregulation of 14-3-3σ correlates with multistage carcinogenesis and poor prognosis of esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  The asymptomatic nature of early-stage esophageal squamous cell carcinoma (ESCC) results in late presentation and consequent dismal prognosis This study characterized 14-3-3σ protein expression in the multi-stage development of ESCC and determined its correlation with clinical features and prognosis.
  
  
  METHODS
  Western blot was used to examine 14-3-3σ protein expression in normal esophageal epithelium (NEE), low grade intraepithelial neoplasia (LGIN), high grade intraepithelial neoplasia (HGIN), ESCC of TNM I to IV stage and various esophageal epithelial cell lines with different biological behavior. Immunohistochemistry was used to estimate 14-3-3σ protein in 110 biopsy samples of NEE, LGIN or HGIN and in 168 ESCC samples all of whom had follow-up data. Support vector machine (SVM) was used to develop a classifier for prognosis.
  
  
  RESULTS
  14-3-3σ decreased progressively from NEE to LGIN, to HGIN, and to ESCC. Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3σ protein compared with non-chemoresistant ESCC cell lines and immortalized NEC. Furthermore, the downregulation of 14-3-3σ correlated significantly with histological grade (P = 0.000) and worse prognosis (P = 0.004). Multivariate Cox regression analysis indicated that 14-3-3σ protein (P = 0.016) and T stage (P = 0.000) were independent prognostic factors for ESCC. The SVM ESCC classifier comprising sex, age, T stage, histological grade, lymph node metastasis, clinical stage and 14-3-3σ, distinguished significantly lower- and higher-risk ESCC patients (91.67% vs. 3.62%, P = 0.000).
  
  
  CONCLUSIONS
  Downregulation of 14-3-3σ arises early in the development of ESCC and predicts poor survival, suggesting that 14-3-3σ may be a biomarker for early detection of high-risk subjects and diagnosis of ESCC. Our seven-feature SVM classifier for ESCC prognosis may help to inform clinical decisions and tailor individual therapy.
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Qi
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Rui-Min
authors.initials: RM
authors.lastname: Liu
authors.affiliation: Huaihe Hospital, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wei
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Wei-Xia
authors.initials: WX
authors.lastname: Chao
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lou
authors.affiliation: Xinxiang Medical University, Xinxiang, Henan, China.
authors.forename: Xiu-Min
authors.initials: XM
authors.lastname: Li
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ma
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Linzhou Cancer Hospital, Linzhou, Henan, P. R. China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: Linzhou Cancer Hospital, Linzhou, Henan, P. R. China.
authors.forename: Hai-Qing
authors.initials: HQ
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cellular and Molecular Immunology, College of Medicine, Henan University, Kaifeng, Henan, P. R. China.
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Ma
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000368:Aged; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060388:Support Vector Machine
chemical_list: D048948:14-3-3 Proteins
references.citation: Clin Cancer Res. 2000 Feb;6(2):541-50
references.pmid: 10690537
references.citation: Mod Pathol. 2005 Mar;18(3):340-8
references.pmid: 15257317
references.citation: Pathol Int. 2004 Aug;54(8):595-602
references.pmid: 15260850
references.citation: Cancer Res. 2013 Apr 1;73(7):2298-309
references.pmid: 23436800
references.citation: Mol Cell Proteomics. 2005 Apr;4(4):555-69
references.pmid: 15644556
references.citation: Nature. 2002 Jun 20;417(6891):871-5
references.pmid: 12075357
references.citation: J Cell Biol. 2000 May 29;149(5):1117-30
references.pmid: 10831615
references.citation: Semin Cell Dev Biol. 2011 Sep;22(7):681-7
references.pmid: 21884813
references.citation: J Cell Sci. 2004 Apr 15;117(Pt 10):1875-84
references.pmid: 15090593
references.citation: Cancer Res. 2000 Aug 15;60(16):4353-7
references.pmid: 10969776
references.citation: Nature. 2007 Mar 15;446(7133):329-32
references.pmid: 17361185
references.citation: J Mol Evol. 1996 Oct;43(4):384-98
references.pmid: 8798343
references.citation: Genes Dev. 2010 May;24(9):947-56
references.pmid: 20439433
references.citation: Int J Oncol. 2004 Dec;25(6):1591-7
references.pmid: 15547695
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6049-54
references.pmid: 10811911
references.citation: Clin Cancer Res. 2004 Apr 15;10(8):2687-93
references.pmid: 15102672
references.citation: Am J Transl Res. 2009 Jun 08;1(4):326-40
references.pmid: 19956445
references.citation: BMC Cancer. 2006 Dec 22;6:296
references.pmid: 17187659
references.citation: Biochim Biophys Acta. 2001 May 28;1519(1-2):1-12
references.pmid: 11406266
references.citation: Pathol Int. 2005 Nov;55(11):707-15
references.pmid: 16271083
references.citation: Br J Cancer. 2004 Sep 13;91(6):1131-8
references.pmid: 15292943
references.citation: Dis Esophagus. 1997 Jul;10(3):159-61
references.pmid: 9280072
references.citation: Anticancer Res. 2010 Dec;30(12):5175-9
references.pmid: 21187508
references.citation: Am J Pathol. 2012 Apr;180(4):1653-62
references.pmid: 22310466
references.citation: Int J Cancer. 2011 Nov 15;129(10):2445-53
references.pmid: 21207417
references.citation: Oncogene. 2004 Dec 2;23(56):9034-41
references.pmid: 15489902
references.citation: Laryngoscope. 2000 Mar;110(3 Pt 1):374-81
references.pmid: 10718422
references.citation: Gut. 2005 Feb;54(2):187-92
references.pmid: 15647178
references.citation: Br J Cancer. 2011 Mar 1;104(5):841-9
references.pmid: 21326238
references.citation: J Mol Evol. 2000 Nov;51(5):446-58
references.pmid: 11080367
references.citation: Dig Dis Sci. 2010 Sep;55(9):2552-60
references.pmid: 20108042
references.citation: Cancer Res. 2002 Apr 1;62(7):2072-6
references.pmid: 11929827
references.citation: Oncogene. 2006 Aug 3;25(33):4559-72
references.pmid: 16786000
references.citation: BMC Cancer. 2011 Feb 03;11:52
references.pmid: 21288367
references.citation: Oncogene. 2001 Jun 7;20(26):3348-53
references.pmid: 11423985
references.citation: Cell Mol Life Sci. 2003 Jun;60(6):1180-99
references.pmid: 12861384
references.citation: Breast Cancer Res. 2007;9(4):R57
references.pmid: 17764565
references.citation: Cancer Res. 2003 Dec 15;63(24):8614-22
references.pmid: 14695172
references.citation: Nat Rev Cancer. 2003 Dec;3(12):931-43
references.pmid: 14737123
references.citation: PLoS One. 2011 Jan 10;6(1):e15864
references.pmid: 21249227
references.citation: Cell Res. 2005 Apr;15(4):228-36
references.pmid: 15857577
references.citation: Cancer Res. 2006 Mar 15;66(6):3248-55
references.pmid: 16540677
references.citation: Biochem J. 2004 Apr 15;379(Pt 2):395-408
references.pmid: 14744259
references.citation: N Engl J Med. 2003 Dec 4;349(23):2241-52
references.pmid: 14657432
references.citation: Oncogene. 2002 Apr 4;21(15):2418-24
references.pmid: 11948426
references.citation: Lancet. 2013 Feb 2;381(9864):400-12
references.pmid: 23374478
references.citation: Nature. 1999 Oct 7;401(6753):616-20
references.pmid: 10524633
references.citation: Oncogene. 2000 Nov 2;19(46):5298-302
references.pmid: 11077447
references.citation: Biochem Biophys Res Commun. 2004 Apr 16;316(4):1156-62
references.pmid: 15044106
references.citation: BMC Cancer. 2010 May 20;10:217
references.pmid: 20487521
references.citation: IEEE Trans Neural Netw. 1999;10(5):988-99
references.pmid: 18252602
references.citation: Clin Cancer Res. 2005 May 1;11(9):3274-9
references.pmid: 15867223
references.citation: J Cell Biochem. 2009 Apr 1;106(5):858-66
references.pmid: 19160382
references.citation: Anticancer Res. 2006 Jul-Aug;26(4B):3105-10
references.pmid: 16886641
references.citation: Mol Cancer Ther. 2006 Apr;5(4):903-12
references.pmid: 16648560
references.citation: Clin Cancer Res. 2004 May 1;10(9):3064-8
references.pmid: 15131044
references.citation: Biochem J. 2004 Jul 15;381(Pt 2):329-42
references.pmid: 15167810
references.citation: Adv Surg. 2007;41:93-119
references.pmid: 17972559
references.citation: Cancer Res. 2003 May 15;63(10):2649-57
references.pmid: 12750293