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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 February 5, 2018
Citation Information: J Clin Invest. 2018;128(3):1010-1025. https://doi.org/10.1172/JCI95802.
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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 7

Correlation of TAZ/YAP and IRS2–p-AKT expression in patients with liver cancer.

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Correlation of TAZ/YAP and IRS2–p-AKT expression in patients with liver ...
(A and B) Scatter plots of log2 (mRNA abundance) values for IRS2 versus TAZ or YAP1 (A) and for IRS2 versus CTGF or CYR61 (B) in tissue specimens from patients with liver cancer or cirrhosis (n = 47) (36), HCC (n = 91) (38), or both HCC and cirrhosis (n = 96) (37). These data were obtained from the Oncomine database and were compared with one another by calculation of the Pearson’s r correlation coefficient. (C and D) Representative IHC staining of TAZ and IRS2 (C) or YAP and IRS2 (D) in HCC patients’ specimens and a comparison of their corresponding levels of expression using the χ2 test (P < 0.001 for C and D). Scale bars: 100 μm. (E and F) Representative images of HCC specimens with associated NAFLD that had high TAZ, YAP, IRS2, and p-AKT (Ser473) IHC intensities compared with HCC specimens not associated with NAFLD (Non-NAFLD) (E). Quantification of the percentage of specimens from E and F. ***P < 0.001, by χ2 test. Scale bars: 50 μm. ND, not detected.
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