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Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer
Sun-Hye Jeong, … , Hueng-Sik Choi, Dae-Sik Lim
Sun-Hye Jeong, … , Hueng-Sik Choi, Dae-Sik Lim
Published March 1, 2018; First published February 5, 2018
Citation Information: J Clin Invest. 2018;128(3):1010-1025. https://doi.org/10.1172/JCI95802.
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Categories: Research Article Hepatology Metabolism

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice. At the molecular level, activation of YAP/TAZ in the liver of Pten–/– Sav1–/– mice amplified AKT signaling through the upregulation of insulin receptor substrate 2 (IRS2) expression. Both ablation of YAP/TAZ and activation of the Hippo pathway could rescue these phenotypes. A high level of YAP/ TAZ expression was associated with a high level of IRS2 expression in human hepatocellular carcinoma (HCC). Moreover, treatment with the AKT inhibitor MK-2206 or knockout of IRS2 by AAV-Cas9 successfully repressed liver tumorigenesis in Pten–/– Sav1–/– mice. Thus, our findings suggest that Hippo signaling interacts with AKT signaling by regulating IRS2 expression to prevent NAFLD and liver cancer progression and provide evidence that impaired crosstalk between these 2 pathways accelerates NAFLD and liver cancer.

Authors

Sun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, Dae-Sik Lim

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Figure 1

Liver-specific deletion of Pten and Sav1 accelerates the development of fatty liver and tumorigenesis.

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Liver-specific deletion of Pten and Sav1 accelerates the development of ...
(A) Livers from 5-month-old mice of the indicated genotypes. DKO (Pten–/– Sav1–/–) livers show advanced tumor development. (B and C) Tumor-free rate (B) and survival rate (C) for mice of the indicated genotypes. (D) Oil red O and PAS staining of livers from 1-month-old mice as well as H&E, Picrosirius red, TUNEL, and F4/80 staining of livers from 3-month-old mice. Scale bars: 100 μm (Oil red O, H&E, and F4/80), 50 μm (PAS), and 200 μm (Picrosirius red and TUNEL). (E) Liver-to-body weight ratio for mice at 2 and 4 months of age. (F) Liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) in the serum of 3-month-old mice of the indicated genotypes. (G) Quantification of apoptotic cells and macrophages following (D) TUNEL and F4/80 staining. Nuclei were stained with DAPI (blue fluorescence). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 versus WT; †P < 0.05, ††P < 0.01, and †††P < 0.001 for the indicated comparisons (1-way ANOVA). (A–G) n = 5 WT mice; (A) n = 5 mice, (B–D) n = 8 mice, and (E–G) n = 3 mice of the other 3 genotypes.
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