Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway

Abstract

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Activation of the AKT/mTOR cascade is one of the most frequent events along hepatocarcinogenesis. mTOR is a serine/threonine kinase and presents in two distinct complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis has not been well characterized, especially in vivo. Pten expression is one of the major mechanisms leading to the aberrant activation of the AKT/mTOR signaling. Here, we show that concomitant downregulation of Pten and upregulation of c-Met occurs in a subset of human HCC, mainly characterized by poor prognosis. Using CRISPR-based gene editing in combination with hydrodynamic injection, Pten was deleted in a subset of mouse hepatocytes (sgPten). We found that loss of Pten synergizes with overexpression of c-Met to promote HCC development in mice (sgPten/c-Met). At the molecular level, sgPten/c-Met liver tumor tissues display increased AKT and mTOR signaling. Using Rictor conditional knockout mice, we demonstrate that sgPten/c-Met-driven HCC development strictly depends on an intact mTORC2 complex. Our findings therefore support the critical role of mTORC2 in hepatocarcinogenesis. sgPten/c-Met mouse model represents a novel valuable system that can be used for the development of targeted therapy against this deadly malignancy.

Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans

“…We discovered that lipogenic proteins are strongly induced in hepatocellular lesions in sgPten/c-Met mice 18. To investigate the requirement of Fasn and mediated de novo lipogenesis in sgPten/c-Met-driven hepatocarcinogenesis, conditional Fasn KO mice ( Fasn fl/fl mice) were employed 19.…”

“…In this manuscript, we investigated the requirement of Fasn in sgPten/c-Met mouse HCC 18. Our results unveil novel biochemical crosstalk between de novo lipogenesis and cholesterol biosynthesis pathways along hepatocarcinogenesis.…”

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma

“…It has been reported that anomalies in the PTEN function may lead to hyperactivation of the PI3K/AKT/mTOR pathway in HCC [70]. Importantly, mutation of PTEN gene or reduced PTEN expression is observed in approximately half of all HCC tumors, suggesting that inactivation of PTEN is involved in the pathogenesis of HCC [70,71]. Furthermore, in a transgenic hepatocyte-specific PTEN deficient mouse model, by 80 weeks of age, 66% of PTEN-deficient mice developed HCC [72].…”

Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma

“…In particular, miRNAs known to target the inhibitors of PI3K/AKT pathway are found in HCC. In this connection, steatosis, hepatomegaly and HCC have been observed in phosphatase and tensin-deficient mice [54] . Several miRNAs are differentially expressed in a high fat diet mouse model during the NAFLD-NASH-HCC transitions [55] .…”