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.

中文翻译：

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河马介导的IRS2 / AKT信号传导抑制可预防肝脂肪变性和肝癌

非酒精性脂肪肝疾病（NAFLD）是肝癌的主要危险因素；因此，其预防是重要的临床目标。磷酸酶和张力蛋白同源物（PTEN）的消融或蛋白激酶Hippo信号通路分别通过激活AKT或转录调节子YAP / TAZ诱导肝癌。然而，到目前为止，在肝肿瘤发生中PTEN / AKT和Hippo / YAP / TAZ途径之间发生串扰的可能性仍不清楚。在这里，我们已经表明，肝脏中PTEN和SAV1的缺失均可促进小鼠NAFLD和肝癌的发展。在分子水平上，Pten ^{– / –} Sav1 ^{– / –}肝脏中的YAP / TAZ激活小鼠通过上调胰岛素受体底物2（IRS2）的表达来扩增AKT信号。YAP / TAZ的切除和Hippo途径的激活都可以挽救这些表型。在人类肝细胞癌（HCC）中，高水平的YAP / TAZ表达与高水平的IRS2表达相关。此外，用AKT抑制剂MK-2206或AAV-Cas9敲除IRS2成功地抑制了Pten ^{– / –} Sav1 ^{– / –}小鼠的肝肿瘤发生。因此，我们的研究结果表明，河马信号传导通过调节IRS2表达来阻止NAFLD和肝癌进展，从而与AKT信号传导相互作用，并提供证据表明这两个途径之间的串扰受损会加速NAFLD和肝癌。