Dataset Information

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.

SUBMITTER: Nam SO

PROVIDER: S-EPMC4402072 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Warburg effect regulated by amphiregulin in the development of colorectal cancer.

Nam Sung Ouk SO Yotsumoto Fusanori F Miyata Kohei K Fukagawa Satoshi S Yamada Hiromi H Kuroki Masahide M Miyamoto Shingo S

Cancer medicine 20150130 4

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 ( ...[more]

PMID: 25644309

Similar Datasets

Project description:Background Accumulating evidence shows that N6-methyladenine (m6A) modulators contribute to the etiology and progression of colorectal cancer (CRC). However, the exact mechanisms of m6A reader involved in glycolytic metabolism remain vague. This article aimed to crosstalk the m6A reader with glycolytic metabolism and reveal a new mechanism for the progression of CRC. Methods The relationship between candidate lncRNA and m6A reader was analyzed by bioinformatics, ISH and IHC assays. In vivo and in vitro studies (including MTT, CFA, trans-well, apoptosis, western blot, qRT-PCR and xenograft mouse models) were utilized to explore the biological functions of these indicators. Lactate detection, ATP activity detection and ECAR assays were used to verify the biological function of the downstream target. The bioinformatics, RNA stability, RIP experiments and RNA pull-down assays were used to explore the potential molecular mechanisms. Results We identified that the crosstalk of the m6A reader IMP2 with long-noncoding RNA (lncRNA) ZFAS1 in an m6A modulation-dependent manner, subsequently augmented the recruitment of Obg-like ATPase 1 (OLA1) and adenosine triphosphate (ATP) hydrolysis and glycolysis during CRC proliferation and progression. Specifically, IMP2 and ZFAS1 are significantly overexpressed with elevated m6A levels in CRC cells and paired CRC cohorts (n = 144). These indicators could be independent biomarkers for CRC prognostic prediction. Notably, IMP2 regulated ZFAS1 expression and enhanced CRC cell proliferation, colony formation, and apoptosis inhibition; thus, it was oncogenic. Mechanistically, ZFAS1 is modified at adenosine +843 within the RGGAC/RRACH element in an m6A-dependent manner. Thus, direct interaction between the KH3–4 domain of IMP2 and ZFAS1 where IMP2 serves as a reader for m6A-modified ZFAS1 and promotes the RNA stability of ZFAS1 is critical for CRC development. More importantly, stabilized ZFAS1 recognizes the OBG-type functional domain of OLA1, which facilitated the exposure of ATP-binding sites (NVGKST, 32–37), enhanced its protein activity, and ultimately accelerated ATP hydrolysis and the Warburg effect. Conclusions Our findings reveal a new cancer-promoting mechanism, that is, the critical modulation network underlying m6A readers stabilizes lncRNAs, and they jointly promote mitochondrial energy metabolism in the pathogenesis of CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01204-0.

Dataset Information

Warburg effect regulated by amphiregulin in the development of colorectal cancer.

Publications

Warburg effect regulated by amphiregulin in the development of colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure