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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

Counteractive effects of pathways oppositely regulated by Myc and xmrk.All but one pathway which were oppositely regulated by Myc and xmrk were counterbalanced and did not show any significant changes in the Myc/xmrk transgenic liver cancer. Red colors indicate up-regulation while green color down-regulation. FDR values are shown in different color gradients as indicated.
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pone.0132319.g004: Counteractive effects of pathways oppositely regulated by Myc and xmrk.All but one pathway which were oppositely regulated by Myc and xmrk were counterbalanced and did not show any significant changes in the Myc/xmrk transgenic liver cancer. Red colors indicate up-regulation while green color down-regulation. FDR values are shown in different color gradients as indicated.

Mentions: Moreover, some pathways showed opposite changes in the Myc- and xmrk-induced zebrafish liver cancers (Fig 2D). Pathways which were up-regulated by Myc but down-regulated by xmrk were cytoplasmic ribosome, mitochondrial ATP synthesis and TNFα/NFκB signaling, while pathways which were up-regulated by xmrk but down-regulated by Myc included GPCR signaling, insulin secretion, chemokine and integrin 1 pathway, and MHC II antigen presentation. These pathways, which were oppositely regulated by Myc and xmrk (Fig 2D), were counterbalanced in the Myc/xmrk transgenic liver cancer (Fig 4).


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)

Counteractive effects of pathways oppositely regulated by Myc and xmrk.All but one pathway which were oppositely regulated by Myc and xmrk were counterbalanced and did not show any significant changes in the Myc/xmrk transgenic liver cancer. Red colors indicate up-regulation while green color down-regulation. FDR values are shown in different color gradients as indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132319.g004: Counteractive effects of pathways oppositely regulated by Myc and xmrk.All but one pathway which were oppositely regulated by Myc and xmrk were counterbalanced and did not show any significant changes in the Myc/xmrk transgenic liver cancer. Red colors indicate up-regulation while green color down-regulation. FDR values are shown in different color gradients as indicated.
Mentions: Moreover, some pathways showed opposite changes in the Myc- and xmrk-induced zebrafish liver cancers (Fig 2D). Pathways which were up-regulated by Myc but down-regulated by xmrk were cytoplasmic ribosome, mitochondrial ATP synthesis and TNFα/NFκB signaling, while pathways which were up-regulated by xmrk but down-regulated by Myc included GPCR signaling, insulin secretion, chemokine and integrin 1 pathway, and MHC II antigen presentation. These pathways, which were oppositely regulated by Myc and xmrk (Fig 2D), were counterbalanced in the Myc/xmrk transgenic liver cancer (Fig 4).

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