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Synergistic Induction of Potential Warburg Effect in Zebrafish Hepatocellular Carcinoma by Co-Transgenic Expression of Myc and xmrk Oncogenes.

Li Z, Zheng W, Li H, Li C, Gong Z - PLoS ONE (2015)

Bottom Line: RNA-Seq analyses revealed distinct changes in many molecular pathways among the three types of liver tumors.In RT-qPCR analyses, the specific pkm2 isoformin Warburg effect was found to be highly enriched in the Myc/xmrk tumors but not in Myc or xmrk tumors, consistent with the observations in many human cancers with Warburg effect.As Pkm2 isoform is generally inactive and causes incomplete glycolysis to favor anabolism and tumor growth, by treatment with a Pkm2-specific activator, TEPP-46, we further demonstrated that activation of Pkm2 suppressed the growth of oncogenic liver as well as proliferation of liver cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, National University of Singapore, 117543, Singapore, Singapore.

ABSTRACT
Previously we have generated inducible liver tumor models by transgenic expression of Myc or xmrk (activated EGFR homolog) oncogenes in zebrafish. To investigate the interaction of the two oncogenes, we crossed the two transgenic lines and observed more severe and faster hepatocarcinogenesis in Myc/xmrk double transgenic zebrafish than either single transgenic fish. RNA-Seq analyses revealed distinct changes in many molecular pathways among the three types of liver tumors. In particular, we found dramatic alteration of cancer metabolism based on the uniquely enriched pathways in the Myc/xmrk tumors. Critical glycolytic genes including hk2, pkm and ldha were significantly up-regulated in Myc/xmrk tumors but not in either single oncogene-induced tumors, suggesting a potential Warburg effect. In RT-qPCR analyses, the specific pkm2 isoformin Warburg effect was found to be highly enriched in the Myc/xmrk tumors but not in Myc or xmrk tumors, consistent with the observations in many human cancers with Warburg effect. Moreover, the splicing factor genes (hnrnpa1, ptbp1a, ptbp1b and sfrs3b) responsible for generating the pkm isoform were also greatly up-regulated in the Myc/xmrk tumors. As Pkm2 isoform is generally inactive and causes incomplete glycolysis to favor anabolism and tumor growth, by treatment with a Pkm2-specific activator, TEPP-46, we further demonstrated that activation of Pkm2 suppressed the growth of oncogenic liver as well as proliferation of liver cells. Collectively, our Myc/xmrk zebrafish model suggests synergetic effect of EGFR and MYC in triggering Warburg effect in the HCC formation and may provide a promising in vivo model for Warburg effect.

No MeSH data available.


Related in: MedlinePlus

Uniquely up- and down-regulated biological process (BP) and KEGG pathways in Myc/xmrk liver tumors.Uniquely up- or down-regulated genes in the Myc/xmrk tumors (1,114 and 359 genes respectively as indicated in Fig 2B) were input into the DAVID online software and top BPs and KEGG pathways are shown. (A) Top significantly up-regulated BPs. (B) Significantly up-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. (C) Significantly down-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. Negative log P-value was plotted against different processes/pathways.
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pone.0132319.g005: Uniquely up- and down-regulated biological process (BP) and KEGG pathways in Myc/xmrk liver tumors.Uniquely up- or down-regulated genes in the Myc/xmrk tumors (1,114 and 359 genes respectively as indicated in Fig 2B) were input into the DAVID online software and top BPs and KEGG pathways are shown. (A) Top significantly up-regulated BPs. (B) Significantly up-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. (C) Significantly down-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. Negative log P-value was plotted against different processes/pathways.

Mentions: Apart from commonly deregulated genes and pathways, a large portion of deregulated genes (30.5% up and 56.6% down) and biological pathways (30.6% up and 27.1% down) in the Myc/xmrk tumors were unique (Fig 2B and 2C).To better understand the biological processes in which these uniquely differentially expressed genes were involved, GO analysis were performed. Both the uniquely up- or down-regulated genes in the Myc/xmrk tumors were used as input for DAVID analysis. As shown in Fig 5A, the top up-regulated BP (Biological Process) items were mostly metabolism-related and included three major groups: glucose metabolism, TCA/cellular respiration and RNA processing. KEGG pathway analysis showed similar metabolic pathways analysis such as Oxidative phosphorylation and Citrate cycle (TCA cycle), as well as Spliceosome and Cell cycle, implying that different RNA processing also occurred in the double transgenic tumor (Fig 5B). In contrast, only one GO item, oxidation reduction, was significantly down-regulated in BP items (data not shown), while KEGG analysis showed down-regulation of metabolism of lipid and amino acid, such as PPAR signaling pathway; Fatty acid metabolism; Tyrosine metabolism; and Glycine, serine and threonine metabolism (Fig 5C). Collectively, these analyses suggested significant deregulation of metabolism-related pathways in the Myc/xmrk tumors.


Synergistic Induction of Potential Warburg Effect in Zebrafish Hepatocellular Carcinoma by Co-Transgenic Expression of Myc and xmrk Oncogenes.

Li Z, Zheng W, Li H, Li C, Gong Z - PLoS ONE (2015)

Uniquely up- and down-regulated biological process (BP) and KEGG pathways in Myc/xmrk liver tumors.Uniquely up- or down-regulated genes in the Myc/xmrk tumors (1,114 and 359 genes respectively as indicated in Fig 2B) were input into the DAVID online software and top BPs and KEGG pathways are shown. (A) Top significantly up-regulated BPs. (B) Significantly up-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. (C) Significantly down-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. Negative log P-value was plotted against different processes/pathways.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492623&req=5

pone.0132319.g005: Uniquely up- and down-regulated biological process (BP) and KEGG pathways in Myc/xmrk liver tumors.Uniquely up- or down-regulated genes in the Myc/xmrk tumors (1,114 and 359 genes respectively as indicated in Fig 2B) were input into the DAVID online software and top BPs and KEGG pathways are shown. (A) Top significantly up-regulated BPs. (B) Significantly up-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. (C) Significantly down-regulated KEGG pathway with P<0.05 and Benjamini value<0.05 cutoff. Negative log P-value was plotted against different processes/pathways.
Mentions: Apart from commonly deregulated genes and pathways, a large portion of deregulated genes (30.5% up and 56.6% down) and biological pathways (30.6% up and 27.1% down) in the Myc/xmrk tumors were unique (Fig 2B and 2C).To better understand the biological processes in which these uniquely differentially expressed genes were involved, GO analysis were performed. Both the uniquely up- or down-regulated genes in the Myc/xmrk tumors were used as input for DAVID analysis. As shown in Fig 5A, the top up-regulated BP (Biological Process) items were mostly metabolism-related and included three major groups: glucose metabolism, TCA/cellular respiration and RNA processing. KEGG pathway analysis showed similar metabolic pathways analysis such as Oxidative phosphorylation and Citrate cycle (TCA cycle), as well as Spliceosome and Cell cycle, implying that different RNA processing also occurred in the double transgenic tumor (Fig 5B). In contrast, only one GO item, oxidation reduction, was significantly down-regulated in BP items (data not shown), while KEGG analysis showed down-regulation of metabolism of lipid and amino acid, such as PPAR signaling pathway; Fatty acid metabolism; Tyrosine metabolism; and Glycine, serine and threonine metabolism (Fig 5C). Collectively, these analyses suggested significant deregulation of metabolism-related pathways in the Myc/xmrk tumors.

Bottom Line: RNA-Seq analyses revealed distinct changes in many molecular pathways among the three types of liver tumors.In RT-qPCR analyses, the specific pkm2 isoformin Warburg effect was found to be highly enriched in the Myc/xmrk tumors but not in Myc or xmrk tumors, consistent with the observations in many human cancers with Warburg effect.As Pkm2 isoform is generally inactive and causes incomplete glycolysis to favor anabolism and tumor growth, by treatment with a Pkm2-specific activator, TEPP-46, we further demonstrated that activation of Pkm2 suppressed the growth of oncogenic liver as well as proliferation of liver cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, National University of Singapore, 117543, Singapore, Singapore.

ABSTRACT
Previously we have generated inducible liver tumor models by transgenic expression of Myc or xmrk (activated EGFR homolog) oncogenes in zebrafish. To investigate the interaction of the two oncogenes, we crossed the two transgenic lines and observed more severe and faster hepatocarcinogenesis in Myc/xmrk double transgenic zebrafish than either single transgenic fish. RNA-Seq analyses revealed distinct changes in many molecular pathways among the three types of liver tumors. In particular, we found dramatic alteration of cancer metabolism based on the uniquely enriched pathways in the Myc/xmrk tumors. Critical glycolytic genes including hk2, pkm and ldha were significantly up-regulated in Myc/xmrk tumors but not in either single oncogene-induced tumors, suggesting a potential Warburg effect. In RT-qPCR analyses, the specific pkm2 isoformin Warburg effect was found to be highly enriched in the Myc/xmrk tumors but not in Myc or xmrk tumors, consistent with the observations in many human cancers with Warburg effect. Moreover, the splicing factor genes (hnrnpa1, ptbp1a, ptbp1b and sfrs3b) responsible for generating the pkm isoform were also greatly up-regulated in the Myc/xmrk tumors. As Pkm2 isoform is generally inactive and causes incomplete glycolysis to favor anabolism and tumor growth, by treatment with a Pkm2-specific activator, TEPP-46, we further demonstrated that activation of Pkm2 suppressed the growth of oncogenic liver as well as proliferation of liver cells. Collectively, our Myc/xmrk zebrafish model suggests synergetic effect of EGFR and MYC in triggering Warburg effect in the HCC formation and may provide a promising in vivo model for Warburg effect.

No MeSH data available.


Related in: MedlinePlus