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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

Synergistic effect of Myc and xmrk oncogenes in transgenic zebrafish survival and liver tumorigenesis.(A,B) Survival curve (A) and gross morphology (B) of oncogene transgenic zebrafish following doxycycline induction at the juvenile stage (starting from 21 dpf). (C) Survival curve of oncogene transgenic zebrafish following doxycycline induction at the adult stage (starting from 3.5 mpf). (D) Gross observation of liver phenotype (left) and histological sections of livers stained by hematoxylin and eosin dyes (right). Abbreviations: X,xmrk; M,Myc; D, doxycycline treatment.
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pone.0132319.g001: Synergistic effect of Myc and xmrk oncogenes in transgenic zebrafish survival and liver tumorigenesis.(A,B) Survival curve (A) and gross morphology (B) of oncogene transgenic zebrafish following doxycycline induction at the juvenile stage (starting from 21 dpf). (C) Survival curve of oncogene transgenic zebrafish following doxycycline induction at the adult stage (starting from 3.5 mpf). (D) Gross observation of liver phenotype (left) and histological sections of livers stained by hematoxylin and eosin dyes (right). Abbreviations: X,xmrk; M,Myc; D, doxycycline treatment.

Mentions: In order to investigate the synergetic effect of Myc and xmrk on zebrafish liver tumorigenesis, heterozygous TO(Myc) and TO(xmrk) were crossed and four groups of fish were resulted: one double-transgenic (M+X+), two single-transgenic (M+X- and M-X+) and one non-transgenic sibling (M-X-). These fish were subjected to doxycycline treatment at juvenile stage (21 dpf). Mortality was first observed in M+X+D+ double-transgenic fish at 4 wpi, whereas no death was observed in the doxycycline-treated single-transgenic fish (M+X-D+ and M-X+D+) and the control groups (M-X-D+) (Fig 1A). The mortality rate of the double transgenic fish quickly reached 25% by 7 wpi, while only small mortalities were observed in the single transgenic fish and no death was found in the controls. At the same time, M+X+D+ fish showed slower growth and obviously enlarged abdomen at 6 wpi (Fig 1B). In comparison, single-transgenic fish showed less severe phenotype and all control fish had normal growth and gross appearance (Fig 1B).


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)

Synergistic effect of Myc and xmrk oncogenes in transgenic zebrafish survival and liver tumorigenesis.(A,B) Survival curve (A) and gross morphology (B) of oncogene transgenic zebrafish following doxycycline induction at the juvenile stage (starting from 21 dpf). (C) Survival curve of oncogene transgenic zebrafish following doxycycline induction at the adult stage (starting from 3.5 mpf). (D) Gross observation of liver phenotype (left) and histological sections of livers stained by hematoxylin and eosin dyes (right). Abbreviations: X,xmrk; M,Myc; D, doxycycline treatment.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132319.g001: Synergistic effect of Myc and xmrk oncogenes in transgenic zebrafish survival and liver tumorigenesis.(A,B) Survival curve (A) and gross morphology (B) of oncogene transgenic zebrafish following doxycycline induction at the juvenile stage (starting from 21 dpf). (C) Survival curve of oncogene transgenic zebrafish following doxycycline induction at the adult stage (starting from 3.5 mpf). (D) Gross observation of liver phenotype (left) and histological sections of livers stained by hematoxylin and eosin dyes (right). Abbreviations: X,xmrk; M,Myc; D, doxycycline treatment.
Mentions: In order to investigate the synergetic effect of Myc and xmrk on zebrafish liver tumorigenesis, heterozygous TO(Myc) and TO(xmrk) were crossed and four groups of fish were resulted: one double-transgenic (M+X+), two single-transgenic (M+X- and M-X+) and one non-transgenic sibling (M-X-). These fish were subjected to doxycycline treatment at juvenile stage (21 dpf). Mortality was first observed in M+X+D+ double-transgenic fish at 4 wpi, whereas no death was observed in the doxycycline-treated single-transgenic fish (M+X-D+ and M-X+D+) and the control groups (M-X-D+) (Fig 1A). The mortality rate of the double transgenic fish quickly reached 25% by 7 wpi, while only small mortalities were observed in the single transgenic fish and no death was found in the controls. At the same time, M+X+D+ fish showed slower growth and obviously enlarged abdomen at 6 wpi (Fig 1B). In comparison, single-transgenic fish showed less severe phenotype and all control fish had normal growth and gross appearance (Fig 1B).

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