title: Warburg effect regulated by amphiregulin in the development of colorectal cancer.
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.
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.
authors: Sung Ouk
authors: SO
authors: Nam
authors: Fusanori
authors: F
authors: Yotsumoto
authors: Kohei
authors: K
authors: Miyata
authors: Satoshi
authors: S
authors: Fukagawa
authors: Hiromi
authors: H
authors: Yamada
authors: Masahide
authors: M
authors: Kuroki
authors: Shingo
authors: S
authors: Miyamoto
mesh_terms: D066258:Amphiregulin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D063646:Carcinogenesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
chemical_list: D066258:Amphiregulin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C403128:MLX protein, human; D005947:Glucose
keywords: Aerobic glycolysis; MLX; amphiregulin; colorectal cancer; glucose metabolism
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