Warburg effect regulated by amphiregulin in the development of colorectal cancer

Cancer Medicine

Sung Ouk Nam²  Fusanori Yotsumoto¹  Kohei Miyata²  Satoshi Fukagawa²  Hiromi Yamada¹  Masahide Kuroki¹ 

[1] Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan;Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

关键词: Aerobic glycolysis;    amphiregulin;    colorectal cancer;    glucose metabolism;    MLX;   

DOI  :  10.1002/cam4.416

来源: Wiley

【 摘 要 】

Abstract

Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality worldwide. Amphiregulin (AREG), a member of the epidermal growth factor family and a rational target for CRC therapy, is essential for the three-dimensional structure of tumor formation. To clone the genes associated with increased AREG expression, we performed a cDNA microarray analysis in two CRC cell lines undergoing two-dimensional (2DC) and three-dimensional culture (3DC). Upregulated (>2.0-fold) and downregulated (<0.5-fold) genes in 3DC compared with 2DC were selected. Pathway analysis using DAVID based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases revealed a number of genes involved in glycolysis. In CRC cells, glucose elevated the expression of GLUT1 and AREG as well as the activity of the hypoxia-inducible factor 1 (HIF-1) luciferase reporter promoter. The suppression of AREG expression reduced the uptake of glucose and production of lactate. Luciferase assay identified a critical regulatory region for AREG expression between −130 and −180 bp upstream of the start site, which contained a carbohydrate response element (ChoRE). Max-like protein X (MLX) bound to ChoRE and enhanced the expression of AREG. Together these data suggest that AREG plays a pivotal role in the development of CRC through activation of the Warburg effect.

【 授权许可】

CC BY   
© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.