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

Nam SO, Yotsumoto F, Miyata K, Fukagawa S, Yamada H, Kuroki M, Miyamoto S - Cancer Med (2015)

Bottom Line: Upregulated (>2.0-fold) and downregulated (<0.5-fold) genes in 3DC compared with 2DC were selected.The suppression of AREG expression reduced the uptake of glucose and production of lactate.Together these data suggest that AREG plays a pivotal role in the development of CRC through activation of the Warburg effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.

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Screening of genes involved in CRC tumorigenesis. (A) mRNA expression indexes of EGFR ligands in CRC cell lines under three-dimensional culture (3DC). The mRNA expression levels of AREG (red bar), HB-EGF (blue bar), EGF (yellow bar), and TGFα (purple bar) are shown. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (B) Levels of soluble EGFR ligands in culture medium under 3DC. Levels of AREG, HB-EGF, EGF, and TGFα proteins per cell were measured by ELISA. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (C) Expression of AREG mRNA in CRC cell lines under 3DC or two-dimensional culture (2DC). The mRNA expression levels of AREG were coded as follows: 3DC, red bar; 2DC, blue bar. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus 2DC. (D) Levels of soluble AREG protein under 2DC or 3DC conditions. The expression levels of AREG protein per cell were measured by ELISA. *P < 0.05 versus 2DC. Data were measured in triplicate and represent mean ± SD. (E) Upregulated (>twofold) and downregulated (<0.5-fold) genes detected by expression microarray analysis. Venn diagrams show the number of common genes in HCT116 and HT29 cells with altered expression in 3DC compared with 2DC. Of these, 537 genes were shared between the two CRC cell lines. The microarray data were obtained from the Gene Expression Omnibus (GEO) database (GEO accession numbers: GSE56738). CRC, colorectal cancer; EGFR, epidermal growth factor receptor; AREG, amphiregulin; HB-EGF, heparin-binding epidermal growth factor-like growth factor; TGFα, transforming growth factor alpha; ELISA, enzyme-linked immunosorbent assay.
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fig01: Screening of genes involved in CRC tumorigenesis. (A) mRNA expression indexes of EGFR ligands in CRC cell lines under three-dimensional culture (3DC). The mRNA expression levels of AREG (red bar), HB-EGF (blue bar), EGF (yellow bar), and TGFα (purple bar) are shown. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (B) Levels of soluble EGFR ligands in culture medium under 3DC. Levels of AREG, HB-EGF, EGF, and TGFα proteins per cell were measured by ELISA. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (C) Expression of AREG mRNA in CRC cell lines under 3DC or two-dimensional culture (2DC). The mRNA expression levels of AREG were coded as follows: 3DC, red bar; 2DC, blue bar. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus 2DC. (D) Levels of soluble AREG protein under 2DC or 3DC conditions. The expression levels of AREG protein per cell were measured by ELISA. *P < 0.05 versus 2DC. Data were measured in triplicate and represent mean ± SD. (E) Upregulated (>twofold) and downregulated (<0.5-fold) genes detected by expression microarray analysis. Venn diagrams show the number of common genes in HCT116 and HT29 cells with altered expression in 3DC compared with 2DC. Of these, 537 genes were shared between the two CRC cell lines. The microarray data were obtained from the Gene Expression Omnibus (GEO) database (GEO accession numbers: GSE56738). CRC, colorectal cancer; EGFR, epidermal growth factor receptor; AREG, amphiregulin; HB-EGF, heparin-binding epidermal growth factor-like growth factor; TGFα, transforming growth factor alpha; ELISA, enzyme-linked immunosorbent assay.

Mentions: To address the significance of AREG as a target for CRC therapy, we examined the mRNA expression and supernatant protein levels of EGFR ligands from CRC cell lines (HCT116, HT29, LoVo, WiDr, CoLo201, and LS180) under 3DC conditions. Results showed a significant increase in AREG mRNA expression and prominent secretion of AREG in 3DC media compared with other EGFR ligands examined (Fig.1A and B). Next, to evaluate alterations in AREG expression associated with tumorigenesis, we examined AREG mRNA expression and supernatant protein levels of CRC cell lines in 2DC and 3DC. AREG mRNA levels and secreted AREG protein levels were significantly increased in 3DC compared with 2DC (Fig.1C and D). These results suggested that AREG might play an important role in CRC tumorigenesis compared with other EGFR ligands.


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

Nam SO, Yotsumoto F, Miyata K, Fukagawa S, Yamada H, Kuroki M, Miyamoto S - Cancer Med (2015)

Screening of genes involved in CRC tumorigenesis. (A) mRNA expression indexes of EGFR ligands in CRC cell lines under three-dimensional culture (3DC). The mRNA expression levels of AREG (red bar), HB-EGF (blue bar), EGF (yellow bar), and TGFα (purple bar) are shown. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (B) Levels of soluble EGFR ligands in culture medium under 3DC. Levels of AREG, HB-EGF, EGF, and TGFα proteins per cell were measured by ELISA. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (C) Expression of AREG mRNA in CRC cell lines under 3DC or two-dimensional culture (2DC). The mRNA expression levels of AREG were coded as follows: 3DC, red bar; 2DC, blue bar. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus 2DC. (D) Levels of soluble AREG protein under 2DC or 3DC conditions. The expression levels of AREG protein per cell were measured by ELISA. *P < 0.05 versus 2DC. Data were measured in triplicate and represent mean ± SD. (E) Upregulated (>twofold) and downregulated (<0.5-fold) genes detected by expression microarray analysis. Venn diagrams show the number of common genes in HCT116 and HT29 cells with altered expression in 3DC compared with 2DC. Of these, 537 genes were shared between the two CRC cell lines. The microarray data were obtained from the Gene Expression Omnibus (GEO) database (GEO accession numbers: GSE56738). CRC, colorectal cancer; EGFR, epidermal growth factor receptor; AREG, amphiregulin; HB-EGF, heparin-binding epidermal growth factor-like growth factor; TGFα, transforming growth factor alpha; ELISA, enzyme-linked immunosorbent assay.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig01: Screening of genes involved in CRC tumorigenesis. (A) mRNA expression indexes of EGFR ligands in CRC cell lines under three-dimensional culture (3DC). The mRNA expression levels of AREG (red bar), HB-EGF (blue bar), EGF (yellow bar), and TGFα (purple bar) are shown. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (B) Levels of soluble EGFR ligands in culture medium under 3DC. Levels of AREG, HB-EGF, EGF, and TGFα proteins per cell were measured by ELISA. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus other EGFR ligands. (C) Expression of AREG mRNA in CRC cell lines under 3DC or two-dimensional culture (2DC). The mRNA expression levels of AREG were coded as follows: 3DC, red bar; 2DC, blue bar. Data were measured in triplicate and represent mean ± SD. *P < 0.05 versus 2DC. (D) Levels of soluble AREG protein under 2DC or 3DC conditions. The expression levels of AREG protein per cell were measured by ELISA. *P < 0.05 versus 2DC. Data were measured in triplicate and represent mean ± SD. (E) Upregulated (>twofold) and downregulated (<0.5-fold) genes detected by expression microarray analysis. Venn diagrams show the number of common genes in HCT116 and HT29 cells with altered expression in 3DC compared with 2DC. Of these, 537 genes were shared between the two CRC cell lines. The microarray data were obtained from the Gene Expression Omnibus (GEO) database (GEO accession numbers: GSE56738). CRC, colorectal cancer; EGFR, epidermal growth factor receptor; AREG, amphiregulin; HB-EGF, heparin-binding epidermal growth factor-like growth factor; TGFα, transforming growth factor alpha; ELISA, enzyme-linked immunosorbent assay.
Mentions: To address the significance of AREG as a target for CRC therapy, we examined the mRNA expression and supernatant protein levels of EGFR ligands from CRC cell lines (HCT116, HT29, LoVo, WiDr, CoLo201, and LS180) under 3DC conditions. Results showed a significant increase in AREG mRNA expression and prominent secretion of AREG in 3DC media compared with other EGFR ligands examined (Fig.1A and B). Next, to evaluate alterations in AREG expression associated with tumorigenesis, we examined AREG mRNA expression and supernatant protein levels of CRC cell lines in 2DC and 3DC. AREG mRNA levels and secreted AREG protein levels were significantly increased in 3DC compared with 2DC (Fig.1C and D). These results suggested that AREG might play an important role in CRC tumorigenesis compared with other EGFR ligands.

Bottom Line: Upregulated (>2.0-fold) and downregulated (<0.5-fold) genes in 3DC compared with 2DC were selected.The suppression of AREG expression reduced the uptake of glucose and production of lactate.Together these data suggest that AREG plays a pivotal role in the development of CRC through activation of the Warburg effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.

Show MeSH
Related in: MedlinePlus