ArticleGastroenterology2013
Akt and mTORC1 have different roles during liver tumorigenesis in mice.
Article in Gastroenterology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 64 citations in OpenAlex.
- Genetic evidence for the causal influence of inflammatory factors on intrahepatic cholangiocarcinoma risk.World journal of gastrointestinal oncology · 2025Article
- Albumin promoter-driven FlpO expression induces efficient genetic recombination in mouse liver.American journal of physiology. Gastrointestinal and liver physiology · 2024Article
- PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1.Journal of translational medicine · 2024Article
- An overview of mouse models of hepatocellular carcinoma.Infectious agents and cancer · 2023Review
- Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma.Pharmaceutics · 2023Review
- Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.British journal of cancer · 2023Article
- Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice.Acta pharmacologica Sinica · 2023Article
- Article
- Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.Nature communications · 2022Article
- Role of mechanistic target of rapamycin in autophagy and alcohol-associated liver disease.American journal of physiology. Cell physiology · 2022Review
- Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular carcinoma.Hepatology (Baltimore, Md.) · 2022Article
- Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma.Cancers · 2021Article
- TSC1/2 mutations-a unique type of mutation suitable for liver transplantation of Hepatocellular carcinoma.Journal of gastrointestinal oncology · 2021Article
- Review
- Autophagy and liver cancer.Clinical and molecular hepatology · 2020Review
- Review
- mTOR up-regulation of SNRPA1 contributes to hepatocellular carcinoma development.Bioscience reports · 2020Article
- Loss of TSC complex enhances gluconeogenesis via upregulation ofProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma.Frontiers in cell and developmental biology · 2020Article
- Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy-Defective Mouse Liver.Hepatology (Baltimore, Md.) · 2019Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND &
aimsPhosphatidylinositide 3-kinase (PI3K) is deregulated in many human tumor types, including primary liver malignancies. The kinase v-akt murine thymoma viral oncogene homolog 1 (Akt) and mammalian target of rapamycin complex (mTORC1) are effectors of PI3K that promote cell growth and survival, but their individual roles in tumorigenesis are not well defined.
methodsIn livers of albumin (Alb)-Cre mice, we selectively deleted tuberous sclerosis (Tsc)1, a negative regulator of Ras homolog enriched in brain and mTORC1, along with Phosphatase and tensin homolog (Pten), a negative regulator of PI3K. Tumor tissues were characterized by histologic and biochemical analyses.
resultsThe Tsc1fl/fl;AlbCre, Ptenfl/fl;AlbCre, and Tsc1fl/fl;Ptenfl/fl;AlbCre mice developed liver tumors that differed in size, number, and histologic features. Livers of Tsc1fl/fl;AlbCre mice did not develop steatosis; tumors arose later than in the other strains of mice and were predominantly hepatocellular carcinomas. Livers of the Ptenfl/fl;AlbCre mice developed steatosis and most of the tumors that formed were intrahepatic cholangiocarcinomas. Livers of Tsc1fl/fl;Ptenfl/fl;AlbCre formed large numbers of tumors, of mixed histologies, with the earliest onset of any strain, indicating that loss of Tsc1 and Pten have synergistic effects on tumorigenesis. In these mice, the combination of rapamycin and MK2206 was more effective in reducing liver cell proliferation and inducing cell death than either reagent alone. Tumor differentiation correlated with Akt and mTORC1 activities; the ratio of Akt:mTORC1 activity was high throughout the course of intrahepatic cholangiocarcinomas development and low during hepatocellular carcinoma development. Compared with surrounding nontumor liver tissue, tumors from all 3 strains had increased activities of Akt, mTORC1, and mitogen-activated protein kinase and overexpressed fibroblast growth factor receptor 1. Inhibition of fibroblast growth factor receptor 1 in Tsc1-null mice suppressed Akt and mitogen-activated protein kinase activities in tumor cells.
conclusionsBased on analyses of knockout mice, mTORC1 and Akt have different yet synergistic effects during the development of liver tumors in mice.
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