Impact of histone deacetylase 1 and metastasis-associated gene 1 expression in esophageal carcinogenesis.

Tomoharu Miyashita,Tetsuo Ohta,Takashi Fujimura,Hirohisa Kitagawa,Koichi Okamoto,Shinichi Nakanuma,Furhawn A Shah,Sachio Fushida,Masatoshi Shoji,Isamu Makino,Katsunobu Oyama,Hidehiro Tajima,Itasu Ninomiya,Hisatoshi Nakagawara,Hironori Hayashi,John W Harmon,Toshifumi Watanabe,Hiroyuki Takamura,Masafumi Inokuchi,Masayoshi Munemoto,Seisho Sakai,Jun Koyama ,Keisuke Nakamura ,Ken‐Ichi Mukaisho

doi:10.3892/ol.2014.2176

Abstract

Animal models are important for the development of novel therapies for esophageal cancer. Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis. The aim of the present study was to evaluate HDAC1 and MTA1 expression in esophageal carcinogenesis in rats. The rats underwent a total gastrectomy followed by esophagojejunostomy to induce chronic duodenal content reflux esophagitis. The rats were sacrificed sequentially at 20, 30, 40 and 50 weeks post-surgery and the esophagi were examined. Immunohistochemical analysis was conducted to assess the expression and localization of HDAC1 and MTA1. At 20 weeks post-surgery, squamous proliferative hyperplasia and Barrett’s metaplasia (BM) were observed. While, adenocarcinoma-associated BM and squamous cell carcinoma were observed at 30–50 weeks post-surgery. The nuclear expression of HDAC1 and MTA1 was observed in all of the stages of squamous carcinogenesis and adenocarcinogenesis, although not in the normal esophageal epithelium. The expression of HDAC1 and MTA1 may be involved in duodenoesophageal reflux-induced neoplastic transformation of the esophageal mucosa into cancer cells with squamous and adeno differentiation.

Highlights

Esophageal squamous cell carcinoma (ESCC) is the dominant type of esophageal cancer worldwide [1]
The incidence of gastroesophageal reflux disease (GERD)‐induced esophageal carcinoma is rising in the USA and the Western world [4,5]
We have pioneered the use of a rat reflux model of esophageal carcinoma, which is based on surgically inducing duodenogastroesophageal reflux akin to GERD in humans without the use of a carcinogen [8,9,10]

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC) is the dominant type of esophageal cancer worldwide [1]. The incidence of esophageal adenocarcinoma (EADC) has been rapidly increasing in the Western world over the last 50 years, in western males [2,3]. The etiology of the increase in the incidence of EADC remains obscure and has prompted further investigation into this clinical issue. The rapid increase of EADC in Western countries has occurred in parallel with an increased prevalence of gastroesophageal reflux disease (GERD) [4,5]. Diet and lifestyle alterations in the Western world have been associated with an increased prevalence of obesity and hiatal hernias, which are known risk factors for GERD and esophageal cancer [5,6]. Gastroduodenal content reflux from GERD induces inflammation‐mediated hyperplasia and metaplasia, and subsequently dysplasia and EADC

Objectives

Methods

Results

Conclusion