Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor
Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor
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DOI：
10.1053/gast.2003.50091
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发表时间：
2003-03-01
期刊：
影响因子：
29.4
通讯作者：
Dimaline, R
中科院分区：
文献类型：
--
作者：
Haigh, CR;Attwood, SEA;Dimaline, R
背景与目的：与Barrett食管发生和恶性进展相关的因素知之甚少。胃泌素是一种有丝分裂原，能够诱导正常和恶性胃肠道粘膜的生长。尚不清楚胃泌素是否能影响巴雷特食管中的细胞事件。研究方法：逆转录聚合酶链反应（RT-PCR）和北方分析胆囊收缩素（CCK 2）受体进行正常，发炎，化生，和恶性食管粘膜。实时PCR定量受体的表达。[I-125]-G17-放射自显影定位粘膜切片中的CCK 2受体。[H-3]-胸苷和溴脱氧尿苷（BrdU）掺入确定了离体孵育的活检标本中响应G17的增殖。在用CCK 2受体转染的OE 33（E）细胞上进行增殖和信号传导研究。结果如下：RT-PCR鉴定了9例对照中的3例、7例食管炎患者中的5例、10例Barrett化生患者中的10例和12例食管腺癌中的7例的受体表达。实时PCR定量表达：10例Barrett's患者的表达水平比12例对照患者高2个数量级。[I1-25]-G17与Barrett粘膜腺体区域内的上皮细胞结合。10 nmol/L G17诱导粘膜活检标本中[3 H]-胸苷掺入增加2倍（n = 7，P = 0.0257，t检验），通过添加CCK 2受体拮抗剂L-740，093消除。1 nmol/L G17诱导OE 33（E）（GR）细胞中[H-3]-胸苷掺入增加1.94 +/- 0.13倍（n = 6，t检验，P = 0.001），L-740，093可消除该作用。结论：胃泌素通过CCK 2受体诱导Barrett粘膜增殖。这可能对通过抑酸治疗升高胃泌素的巴雷特食管患者的管理有影响。
Background & Aims: Factors associated with the development and malignant progression of Barrett's esophagus are poorly understood. Gastrin is a mitogen capable of inducing growth in normal and malignant gastrointestinal mucosa. It is unknown whether gastrin can influence cellular events in the esophagus in Barrett's. Methods: Reverse-transcription polymerase chain reaction (RT-PCR) and northern analysis for the cholecystokinin (CCK2) receptor were performed on normal, inflamed, metaplastic, and malignant esophageal mucosa. Real-time PCR quantified expression of the receptor. [I-125]-G17-autoradiography localized the CCK2 receptor in mucosal sections. [H-3]-thymidine and bromodeoxyuridine (BrdU) incorporation determined proliferation in response to G17 in biopsy specimens incubated ex vivo. Proliferation and signaling studies were performed on OE33(E) cells transfected with the CCK2 receptor. Results: RT-PCR identified receptor expression in 3 of 9 controls, 5 of 7 patients with esophagitis, 10 of 10 patients with Barrett's metaplasia, and 7 of 12 esophageal adenocarcinomas. Real-time PCR quantified expression in :10 patients with Barrett's showing a level of expression 2 orders of magnitude higher than in 12 control patients. [I1-25]-G17 bound to epithelia within glandular regions of Barrett's mucosa. Ten nmol/L G17 induced a 2-fold (n = 7, P = 0.0257, t test) increase in [3H]-thymidine incorporation in mucosal biopsy specimens, abolished by the addition of the CCK2 receptor antagonist L-740, 093. One nmol/L G17 induced a 1.94- +/- 0.13-fold (n = 6, t test, P = 0.001) increase in [H-3]-thymidine incorporation in OE33(E)(GR) cells, abolished by L-740, 093. Conclusions: Gastrin induces proliferation via the CCK2 receptor in Barrett's mucosa. This may have implications for the management of patients with Barrett's esophagus in whom gastrin is elevated by acid-suppression therapy.