J Cancer 2019; 10(22):5597-5607. doi:10.7150/jca.30050

Research Paper

Role of Kruppel-Like Factor 5 in Deoxycholic Acid-Mediated Intestinal Transdifferentiation of Esophageal Squamous Epithelium

Yiju Xia1, Yu Fang2, Haoxiang Zhang1, Caifei Shen1, Pu Wang1, Wu Yan1, Jingwen Li1, Yin Xu1, Shunzi Shao1, Yafei Zhang1, Xiaona Yu1, Zhihong Peng1, Guiyong Peng1, Wensheng Chen1, Dianchun Fang1✉

1. Department of Gastroenterology, Southwest Hospital, Army Medical University, Chongqing, 400038, P.R. China
2. Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China

Abstract

Barrett's esophagus (BE) is an acquired condition in which normal squamous epithelium is replaced with metaplastic columnar epithelium as a consequence of gastroesophageal reflux disease. BE is known as a precursor of esophageal adenocarcinoma. Currently, the molecular mechanism underlying epithelial metaplasia in BE patients remains unknown. Therefore, we investigated the role of Krüppel-like factor 5 (KLF5) signaling in the initiation of BE-associated metaplasia. Sprague-Dawley (SD) rats were used to create a surgical model of bile reflux injury. Immunohistochemistry was performed to analyze human and mouse esophageal specimens. Human esophageal squamous epithelial (HET-1A) cells were treated with bile acid and used in transfection experiments. Quantitative real-time PCR and western blot analysis were performed to detect the expression of KLF5, CDX2, MUC2 and villin.

Epithelial tissue from both the rat BE model and human BE patients strongly expressed KLF5, CDX2, MUC2, and villin. Bile acid treatment also increased the expression of KLF5, CDX2, MUC2 and villin in esophageal epithelial cells in a time-dependent manner. Moreover, siRNA-mediated knockdown of KLF5 blocked the expression of CDX2, MUC2 and villin, but transfection of a KLF5 expression vector into esophageal epithelial cells promoted their transdifferentiation into columnar-like cells, as demonstrated by increased expression of the intestinal markers CDX2, MUC2 and villin. Thus, in addition to its function as a transcription factor, KLF5 may be linked to an increased risk of BE development.

Keywords: Barrett's esophagus, transdifferentiation, KLF5, deoxycholic acid

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How to cite this article:
Xia Y, Fang Y, Zhang H, Shen C, Wang P, Yan W, Li J, Xu Y, Shao S, Zhang Y, Yu X, Peng Z, Peng G, Chen W, Fang D. Role of Kruppel-Like Factor 5 in Deoxycholic Acid-Mediated Intestinal Transdifferentiation of Esophageal Squamous Epithelium. J Cancer 2019; 10(22):5597-5607. doi:10.7150/jca.30050. Available from http://www.jcancer.org/v10p5597.htm