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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

RNA-Seq analyses of Myc-, xmrk-, Myc/xmrk-induced liver tumors.(A) Hierarchical clustering of the eight RNA-Seq samples.(B) Venn diagram of up- and down-regulated transcripts in the three liver tumors. (C) Venn diagram of up-and down-regulated canonical pathways in the three liver tumors. (D) Venn diagram of pathways with opposite directions between Myc- and xmrk-induced liver tumors.
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pone.0132319.g002: RNA-Seq analyses of Myc-, xmrk-, Myc/xmrk-induced liver tumors.(A) Hierarchical clustering of the eight RNA-Seq samples.(B) Venn diagram of up- and down-regulated transcripts in the three liver tumors. (C) Venn diagram of up-and down-regulated canonical pathways in the three liver tumors. (D) Venn diagram of pathways with opposite directions between Myc- and xmrk-induced liver tumors.

Mentions: In order to compare the molecular basis of Myc and xmrk induced liver tumors and to investigate the molecular mechanism of the synergy of Myc and xmrk, RNA-Seq was carried out on liver samples from five control groups (M-X-D-, M+X-D-, M-X+D-, M+X+D- and M-X-D+) and three liver tumor groups (M+X+D+, M+X-D+ and M-X+D+). 11–18 million tags were generated from each sample and these tags were mapped to the zebrafish RefSeq mRNA database with mapping efficiency ranged from 22% to 44% (S2 Table). Hierarchical clustering was performed using the entire transcriptome (Fig 2A). Pearson correlation indicated that the five control samples were very similar and they were well separated from the three tumor samples.


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)

RNA-Seq analyses of Myc-, xmrk-, Myc/xmrk-induced liver tumors.(A) Hierarchical clustering of the eight RNA-Seq samples.(B) Venn diagram of up- and down-regulated transcripts in the three liver tumors. (C) Venn diagram of up-and down-regulated canonical pathways in the three liver tumors. (D) Venn diagram of pathways with opposite directions between Myc- and xmrk-induced liver tumors.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132319.g002: RNA-Seq analyses of Myc-, xmrk-, Myc/xmrk-induced liver tumors.(A) Hierarchical clustering of the eight RNA-Seq samples.(B) Venn diagram of up- and down-regulated transcripts in the three liver tumors. (C) Venn diagram of up-and down-regulated canonical pathways in the three liver tumors. (D) Venn diagram of pathways with opposite directions between Myc- and xmrk-induced liver tumors.
Mentions: In order to compare the molecular basis of Myc and xmrk induced liver tumors and to investigate the molecular mechanism of the synergy of Myc and xmrk, RNA-Seq was carried out on liver samples from five control groups (M-X-D-, M+X-D-, M-X+D-, M+X+D- and M-X-D+) and three liver tumor groups (M+X+D+, M+X-D+ and M-X+D+). 11–18 million tags were generated from each sample and these tags were mapped to the zebrafish RefSeq mRNA database with mapping efficiency ranged from 22% to 44% (S2 Table). Hierarchical clustering was performed using the entire transcriptome (Fig 2A). Pearson correlation indicated that the five control samples were very similar and they were well separated from the three tumor samples.

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