大鼠和人食管腺癌中的白三烯A4水解酶及贝司他汀的抑制作用

Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin.

作者信息

Chen Xiaoxin, Li Ning, Wang Su, Wu Nan, Hong Jungil, Jiao Xiaolong, Krasna Mark J, Beer David G, Yang Chung S

机构信息

Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.

出版信息

J Natl Cancer Inst. 2003 Jul 16;95(14):1053-61. doi: 10.1093/jnci/95.14.1053.

DOI:10.1093/jnci/95.14.1053

PMID:12865451

Abstract

BACKGROUND

Esophageal adenocarcinoma (EAC) is increasing at the most rapid rate of any cancer in the United States. An esophagogastroduodenal anastomosis (EGDA) surgical model in rats mimics human gastroesophageal reflux and results in EAC. Leukotriene A4 hydrolase (LTA4H), a protein overexpressed in EAC in this model, is a rate-limiting enzyme in the biosynthesis of leukotriene B4 (LTB4), a potent inflammatory mediator. We used this model and human EAC and non-tumor tissues to elucidate the expression pattern of LTA4H and to evaluate it as a target for chemoprevention.

METHODS

LTA4H expression was examined by western blotting and immunohistochemistry. The functional role of LTA4H in carcinogenesis was investigated by use of an LTA4H inhibitor, bestatin, in the rat EGDA model. All statistical tests were two-sided.

RESULTS

LTA4H was overexpressed in all 10 rat EACs examined, compared with its level in normal rat tissue; it was also overexpressed in four of six human EAC tumor samples, compared with its level in adjacent non-tumor tissue. In tissue sections from 20 EGDA rats and 92 patients (86 with EAC, one with dysplasia, and five with columnar-lined esophagus), LTA4H was expressed in infiltrating inflammatory cells and overexpressed in the columnar cells of preinvasive lesions and cancers, especially in well-differentiated EACs, as compared with the basal cells of the normal esophageal squamous epithelium. Bestatin statistically significantly inhibited LTB4 biosynthesis in the esophageal tissues of EGDA rats (without bestatin = 8.28 ng/mg of protein; with bestatin = 4.68 ng/mg of protein; difference = 3.60, 95% CI = 1.59 to 5.61; P = .002) and reduced the incidence of EAC in the EGDA rats from 57.7% (15 of 26 rats) to 26.1% (6 of 23 rats) (difference = 31.6%, 95% CI = 0.3% to 56.2%; P = .042).

CONCLUSION

LTA4H overexpression appears to be an early event in esophageal adenocarcinogenesis and is a potential target for the chemoprevention of EAC.

摘要

背景

食管腺癌（EAC）在美国所有癌症中发病率增长最为迅速。大鼠食管胃十二指肠吻合术（EGDA）手术模型可模拟人类胃食管反流并导致EAC。白三烯A4水解酶（LTA4H）是该模型中在EAC中过度表达的一种蛋白质，它是强效炎症介质白三烯B4（LTB4）生物合成中的限速酶。我们利用该模型以及人类EAC和非肿瘤组织来阐明LTA4H的表达模式，并将其评估为化学预防的靶点。

方法

通过蛋白质印迹法和免疫组织化学检测LTA4H的表达。在大鼠EGDA模型中使用LTA4H抑制剂贝司他汀研究LTA4H在致癌过程中的功能作用。所有统计检验均为双侧检验。

结果

与正常大鼠组织中的水平相比，在所检测的所有10例大鼠EAC中LTA4H均过度表达；与相邻非肿瘤组织中的水平相比，在6例人类EAC肿瘤样本中的4例中LTA4H也过度表达。在20只EGDA大鼠和92例患者（86例EAC、1例发育异常和5例柱状上皮化生食管）的组织切片中，与正常食管鳞状上皮的基底细胞相比，LTA4H在浸润性炎症细胞中表达，并在癌前病变和癌症的柱状细胞中过度表达，尤其是在高分化EAC中。贝司他汀在统计学上显著抑制了EGDA大鼠食管组织中LTB4的生物合成（无贝司他汀时 = 8.28 ng/mg蛋白质；有贝司他汀时 = 4.68 ng/mg蛋白质；差异 = 3.60，95%CI = 1.59至5.61；P = 0.002），并将EGDA大鼠中EAC的发生率从57.7%（26只大鼠中的15只）降低至26.1%（23只大鼠中的6只）（差异 = 31.6%，95%CI = 0.3%至56.2%；P = 0.042）。