Nitric oxide-mediated invasion in Barrett's high-grade dysplasia and adenocarcinoma.
Nitric oxide (NO) has been shown to induce double strand DNA breaks in Barrett's oesophagus (BO) and in other cancers has a role in invasion. The specific aims of this study were to investigate whether NO can induce invasion in cells representative of different stages of Barrett's progression and to determine possible underlying mechanisms. Physiological concentrations of NO that mimic luminal production of NO from dietary sources enhanced invasion in cell lines from high-grade dysplasia (GihTERT) and oesophageal adenocarcinoma (FLO) but not a non-dysplastic Barrett's cell line (QhTERT). Real-time reverse transcription-polymerase chain reaction revealed that NO induced expression of matrix metalloproteinase (MMP)-1, -3, -7, -9 and -10 and tissue inhibitor of metalloproteinase (TIMP)-1, -2 and -3 in these cell lines. Furthermore, ex vivo treatment of Barrett's biopsy samples with NO induced increases in MMP-1 and TIMP-1 expression, suggesting that NO enhances invasion through deregulating MMP and TIMP expression in epithelial cells. In keeping with these findings, microarray analysis and immunohistochemistry performed on biopsy samples showed enhanced expression of MMP-1, -3, -7 and -10 and TIMP-1 in the progression from non-dysplastic BO to adenocarcinoma, although this could not be directly attributed to the effect of NO. Thus, NO may play a role in Barrett's carcinogenesis through deregulating MMP and TIMP expression to enhance invasive potential.
Clemons
Nicholas J
NJ
Medical Research Council Cancer Cell Unit, Hutchison/Medical Research Council Centre, Hills Road, Cambridge, CB2 0XZ, UK.
Shannon
Nicholas B
NB
Abeyratne
Lakshi R
LR
Walker
C E
CE
Saadi
Amel
A
O'Donovan
Maria L
ML
Lao-Sirieix
Pierre P
PP
Fitzgerald
Rebecca C
RC
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D001471:Barrett Esophagus / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009569:Nitric Oxide / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D009569:Nitric Oxide; D020781:Matrix Metalloproteinase 1