title: A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis.
abstract: A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCϵ) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCϵ and this SNP in esophageal carcinogenesis, we analyzed PLCϵ genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCϵ mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59-22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33-1.64 in low-incidence area; P = 0.008). In conclusion, the PLCϵ gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCϵ mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.
authors: Department of Pathology, Xinxiang Medical University, Xinxiang, China; Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors: Li-Dong
authors: LD
authors: Wang
authors: Xiuli
authors: X
authors: Bi
authors: Xin
authors: X
authors: Song
authors: Nicole M
authors: NM
authors: Pohl
authors: Yulan
authors: Y
authors: Cheng
authors: Yixing
authors: Y
authors: Zhou
authors: Stephen
authors: S
authors: Shears
authors: Emmanuel
authors: E
authors: Ansong
authors: Mengtao
authors: M
authors: Xing
authors: Shaomeng
authors: S
authors: Wang
authors: Xiao-Chun
authors: XC
authors: Xu
authors: Peng
authors: P
authors: Huang
authors: Liyan
authors: L
authors: Xu
authors: Liang
authors: L
authors: Wang
authors: Zongmin
authors: Z
authors: Fan
authors: Xueke
authors: X
authors: Zhao
authors: Huali
authors: H
authors: Dong
authors: Stephen J
authors: SJ
authors: Meltzer
authors: Ivan
authors: I
authors: Ding
authors: Wancai
authors: W
authors: Yang
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004941:Esophagitis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D009367:Neoplasm Staging; D054801:Phosphoinositide Phospholipase C / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon
keywords: esophageal cancer; esophagitis; phospholipase C epsilon
references: J Biol Chem. 2001 Dec 21;276(51):48257-61
references: 11641393
references: EMBO J. 2001 Feb 15;20(4):743-54
references: 11179219
references: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15543-8
references: 17878312
references: J Biol Chem. 2001 Jan 26;276(4):2758-65
references: 11022047
references: J Immunol. 2010 Jan 15;184(2):993-1002
references: 20007527
references: Mol Nutr Food Res. 2008 Nov;52(11):1289-99
references: 18435490
references: Trends Cell Biol. 2006 Dec;16(12):640-8
references: 17085049
references: Mol Cell. 2006 Feb 17;21(4):495-507
references: 16483931
references: J Biol Chem. 2004 Nov 12;279(46):47992-7
references: 15322077
references: Nat Genet. 2010 Sep;42(9):764-7
references: 20729852
references: J Biol Chem. 2008 Jan 4;283(1):341-349
references: 17956867
references: Adv Enzyme Regul. 2009;49(1):54-8
references: 19534025
references: Lancet. 1982 Apr 17;1(8277):876-9
references: 6122101
references: Biochem J. 2004 Feb 15;378(Pt 1):129-39
references: 14567755
references: Nat Rev Cancer. 2010 May;10(5):342-52
references: 20414202
references: J Biol Chem. 2009 Jan 16;284(3):1514-22
references: 18957419
references: Cancer Res. 2004 Dec 15;64(24):8808-10
references: 15604236
references: J Biol Chem. 2006 Feb 3;281(5):2639-48
references: 16314422
references: Cancer Res. 2008 Jan 1;68(1):64-72
references: 18172297
references: Oncogene. 2002 Nov 21;21(53):8105-13
references: 12444546
references: Carcinogenesis. 2009 Aug;30(8):1424-32
references: 19458037
references: Ann Surg Oncol. 2012 Jul;19(7):2403-10
references: 22203178
references: Mol Pharmacol. 2006 Jun;69(6):2068-75
references: 16554409
references: Nat Genet. 2010 Sep;42(9):759-63
references: 20729853
references: Annu Rev Biochem. 1997;66:475-509
references: 9242915
references: J Biol Chem. 2003 Oct 17;278(42):41253-8
references: 12900402