An integrative genomic approach in oesophageal cells identifies TRB3 as a bile acid responsive gene, downregulated in Barrett's oesophagus, which regulates NF-κB activation and cytokine levels

被引:27
作者
Duggan, Shane P. [1 ,2 ]
Behan, Fiona M. [1 ,2 ]
Kirca, Murat [1 ,2 ,3 ]
Smith, Sinead [1 ,2 ]
Reynolds, John V. [4 ,5 ]
Long, Aideen [1 ,2 ]
Kelleher, Dermot [1 ,2 ,3 ]
机构
[1] Trinity Coll Dublin, Dept Clin Med, Dublin 2, Ireland
[2] Trinity Coll Dublin, Inst Mol Med, Dublin 2, Ireland
[3] St James Hosp, Dept Gastroenterol, Dublin 8, Ireland
[4] Trinity Coll Dublin, Dept Surg, Dublin 2, Ireland
[5] Trinity Coll Dublin, Inst Mol Med, Dublin 2, Ireland
关键词
GROWTH-FACTOR RECEPTOR; DEOXYCHOLIC-ACID; LOW PH; NEOADJUVANT CHEMORADIOTHERAPY; ADENOCARCINOMA SEQUENCE; COLON CARCINOGENESIS; OXIDATIVE STRESS; DNA-DAMAGE; IN-VITRO; METAPLASIA;
D O I
10.1093/carcin/bgq036
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Reflux of gastroduodenal contents and consequent inflammatory responses are associated with the development of Barrett's oesophagus (BO) and the promotion of oesophageal adenocarcinoma (OAC). Deregulation of inflammatory processes is a hallmark of oesophageal cancer. In this study, we aimed to investigate (i) the transcriptional responses to deoxycholic acid (DCA) in cell lines representative of either end of the oesophageal cancer sequence, (ii) the expression of DCA-regulated genes in data charting oesophageal carcinogenesis and (iii) the impact of these genes on oesophageal inflammatory signalling. Gene expression microarrays were utilized to demonstrate differential transcriptional responses between squamous (HET-1A) and adenomatous (SKGT4) cell lines exposed to DCA. Differential basal and DCA-inducible expression of cytokines such as interleukin (IL) 8 was observed between both cell types. A cohort of DCA-regulated genes specific to each cell type was identified in microarray experimentation and subsequently validated. Cell type-specific genes included TRB3, CXCL14, GDF15 and LIF in HET-1A cells, with COX2-, ESM1-, URHF1- and IL1 alpha-and IL1 beta-specific expression in SKGT4 cells. Over 30% of the genes altered in BO and OAC were shown to be regulated by DCA utilizing an integrative genomic approach. One such gene, tribbles-homology-3 (TRB3) was induced specifically in HET-1A cells, absent in SKGT4 cells and decreased in BO samples in silico and in vivo. Inhibition and re-introduction of TRB3 in HET-1A and SKGT4 cells, respectively, demonstrated the ability of TRB3 to regulate inflammatory signalling through nuclear factor-kappaB. This study identifies mechanisms through which bile acids such as DCA, in conjunction with the loss of key signalling molecules, could regulate oesophageal metaplasticity.
引用
收藏
页码:936 / 945
页数:10
相关论文
共 36 条
[1]
NF-κB activation in Esophageal adenocarcinoma -: Relationship to Barrett's metaplasia, survival, and response to neoadjuvant chemoradiotherapy [J].
Abdel-Latif, MMM ;
O'Riordan, J ;
Windle, HJ ;
Carton, E ;
Ravi, N ;
Kelleher, D ;
Reynolds, JV .
ANNALS OF SURGERY, 2004, 239 (04) :491-500
[2]
Activated nuclear factor-kappa B and cytokine profiles in the esophagus parallel tumor regression following neoadjuvant chemoradiotherapy [J].
Abdel-Latif, MMM ;
O'Riordan, JM ;
Ravi, N ;
Kelleher, D ;
Reynolds, JV .
DISEASES OF THE ESOPHAGUS, 2005, 18 (04) :246-252
[3]
Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis [J].
Ancrile, Brooke ;
Lim, Kian-Huat ;
Counter, Christopher M. .
GENES & DEVELOPMENT, 2007, 21 (14) :1714-1719
[4]
PHOSPHATIDYLCHOLINE HYDROLYSIS ACTIVATES NF-KAPPA-B AND INCREASES HUMAN-IMMUNODEFICIENCY-VIRUS REPLICATION IN HUMAN MONOCYTES AND T-LYMPHOCYTES [J].
ARENZANASEISDEDOS, F ;
FERNANDEZ, B ;
DOMINGUEZ, I ;
JACQUE, JM ;
THOMAS, D ;
DIAZMECO, MT ;
MOSCAT, J ;
VIRELIZIER, JL .
JOURNAL OF VIROLOGY, 1993, 67 (11) :6596-6604
[5]
Bile acids as carcinogens in human gastrointestinal cancers [J].
Bernstein, H ;
Bernstein, C ;
Payne, CM ;
Dvorakova, K ;
Garewal, H .
MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH, 2005, 589 (01) :47-65
[6]
SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia [J].
Bowers, AJ ;
Scully, S ;
Boylan, JF .
ONCOGENE, 2003, 22 (18) :2823-2835
[7]
p8 upregulation sensitizes astrocytes to oxidative stress [J].
Carracedo, A ;
Egia, A ;
Guzmán, M ;
Velasco, G .
FEBS LETTERS, 2006, 580 (06) :1571-1575
[8]
TRB3:: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver [J].
Du, KY ;
Herzig, S ;
Kulkarni, RN ;
Montminy, M .
SCIENCE, 2003, 300 (5625) :1574-1577
[9]
Low pH induces co-ordinate regulation of gene expression in oesophageal cells [J].
Duggan, SP ;
Gallagher, WM ;
Fox, EJP ;
Abdel-Latif, MM ;
Reynolds, JV ;
Kelleher, D .
CARCINOGENESIS, 2006, 27 (02) :319-327
[10]
Activation of the interleukin-6/STAT 3 antiapoptotic pathway in esophageal cells by bile acids and low pH: Relevance to Barrett's esophagus [J].
Dvorak, Katerina ;
Chavarria, Melissa ;
Payne, Claire M. ;
Ramsey, Lois ;
Crowley-Weber, Cara ;
Dvorakova, Barbora ;
Dvorak, Bohuslav ;
Bernstein, Harris ;
Holubec, Hana ;
Sampliner, Richard E. ;
Bernstein, Carol ;
Prasad, Anil ;
Green, Sylvan B. ;
Garewal, Harinder .
CLINICAL CANCER RESEARCH, 2007, 13 (18) :5305-5313