Comparing mRNA expression of Myc/NrasG12V and Myc/Akt1 driven liver tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA681524 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13165900.fastq.gz | Fastqsanger.gz | |||
| SRR13165901.fastq.gz | Fastqsanger.gz | |||
| SRR13165902.fastq.gz | Fastqsanger.gz | |||
| SRR13165897.fastq.gz | Fastqsanger.gz | |||
| SRR13165898.fastq.gz | Fastqsanger.gz |
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Project description:To analyze mRNA expression of Myc/NrasG12V and Myc/Akt1 driven liver tumors (HCC), we generated HCCs with elevated MYC expression and activated Raf-MEK-ERK or Akt1 signaling. To trigger tumor development, we co-delivered transposable elements encoding for Myc and oncogenic NrasG12V or myristoylated Akt1 via hydrodynamic injection into the hepatocytes of C57BL/6 wildtype mice and analyzed the transcriptomes of the developed tumors.
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Project description:Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC is a key molecular event in HCC. In this study, we explored the roles of TSC/mTORC1 and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had minimal impact on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablating TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E act downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.
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