雷帕霉素靶蛋白抑制剂对胃食管反流病大鼠 Barrett 食管及食管腺癌的预防作用。

Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease.

机构信息

Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

出版信息

Ann Surg. 2013 Jul;258(1):82-8. doi: 10.1097/SLA.0b013e318270500d.

DOI:10.1097/SLA.0b013e318270500d

PMID:23108119

Abstract

BACKGROUND

Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis.

METHODS

GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed.

RESULTS

Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene).

CONCLUSIONS

Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.

摘要

背景

激活的刺猬（Hh）信号通路与 Barrett 食管（BE）和食管腺癌（EAC）的发展有关。我们假设，用 smoothened（Smo）抑制剂阻断 Hh 通路可以预防 Levrat 模型中 BE/EAC 的发展，该模型中诱导的胃食管反流（GDER）导致食管癌变。

方法

在 6-8 周龄雄性 Sprague-Dawley 大鼠中诱导 GDER。Smo 抑制剂（10mg/kg/d）在术后第 10 周到第 16 周、第 18 周到第 22 周和第 24 周到第 28 周口服给予，并在第 28 周处死大鼠。主要观察指标为 BE 和 EAC 的发生率。为了研究 Smo 抑制对肿瘤组织的潜在治疗作用，进行了 Ki-67 和 caspase 3 的半定量免疫组织化学分析。在发生癌症的治疗动物中，分析了基因表达。

结果

48 只对照组中有 38 只和 46 只治疗组中有 32 只动物存活至 28 周。BE 中的印度刺猬 mRNA（一种跨膜受体 patched 1 的配体）表达比正常食管组织高 184 倍（P = 0.0239），EAC 中高 99 倍（P = 0.0004）。与对照组相比，治疗组 BE 和 EAC 的发生率分别降低了 35.7%（相对风险降低 36%；P = 0.0015）和 36%（相对风险降低 62%；P = 0.0033）。与未经治疗的 EAC 相比，Ki-67 的表达下调（P = 0.04），而治疗组的 EAC 中 cleaved caspase 3 没有差异（P = 0.398）。在 84 个已知与癌症药物耐药性相关的基因中，有 50 个在治疗组的 EAC 中失调（每个基因的 P < 0.05）。