We show that MYC overexpression (MYC<sup>Tg</sup>) synergizes with KRAS<sup>G12D</sup> to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRAS<sup>G12D</sup> alone.
To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden.
C57BL/6 mice received hydrodynamic tail-vein injections of transposons encoding HRAS<sup>G12V</sup> and a short hairpin RNA (shRNA) to down-regulate p53, or those encoding HRAS<sup>G12V</sup> and MYC, or those encoding HRAS<sup>G12V</sup> and TAZ<sup>S89A</sup>, to induce liver tumor formation; mice were also given injections of transposons encoding SMAD7 or shRNA against SMAD2, SMAD3, SMAD4, or SNAI1 (Snail), with or without ectopic expression of Snail.
Overexpression of IGF2 accelerates formation of liver tumors in mice with hepatic expression of MYC and AKT1, via activation of IGF1 receptor signaling.
Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.
Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase.
Treatment of the human hepatoma cell line HepG2 with hepatic growth factor (Hgf) caused c-Myc protein induction and transcriptional up-regulation of candidate genes, albeit at different levels when individual genes were compared.
We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC.
Consistent with the recently reported association between c-MYC overexpression and induction of telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in telomerase activity.
Hence, chloroform prevented the hypomethylation and increased mRNA expression of the c-myc gene and the promotion of liver tumors by DCA, while enhancing DCA-promotion of kidney tumors.
Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis.
The expression of the c-myc gene has previously been shown to be elevated and deregulated in the human hepatoma cell line Hep G2 (B. E. Huber and S. S. Thorgeirsson, Cancer Res., 47: 3414-3420, 1987).