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      HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway

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          Abstract

          Non-alcoholic fatty liver disease (NAFLD) is a relevant risk factor for developing hepatocellular carcinoma (HCC). Steatohepatitic HCC (SH-HCC), characterized by HCC with steatosis, is influenced by lipid metabolism disorders. A hypoxic microenvironment is common in HCC and affects lipid metabolism. However, whether hypoxia-induced HIF-2α upregulation exacerbates lipid accumulation to contribute to SH-HCC progression remains unclear. In this study, we demonstrated that HIF-2α was elevated in tissues from NAFLD-HCC patients and was associated with survival. Under hypoxic conditions, upregulated HIF-2α was accompanied by lipid accumulation and PI3K-AKT-mTOR pathway activation. HIF-2α knockdown (KD) in steatotic HCC ameliorated triglyceride accumulation and steatosis. HIF-2α-KD steatotic HCC showed minimal lipid synthesis in a hypoxic environment, which contributes to a reduction in malignant behaviours. However, treatment with MHY1485 restored these behaviours. STAM mice, a mouse model that develops NAFLD-HCC, exhibit more rapid tumour progression upon exposure to hypoxia. STAM mice treated with INK-128 presented abrogated mTOR expression and tumour progression under hypoxic conditions with lower triglycerides and steatosis. In conclusion, in a hypoxic microenvironment, HIF-2α upregulation promotes steatotic HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Therefore, HIF-2α can be a biomarker and target in developing specific therapeutic measures for NAFLD-HCC patients.

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          Most cited references34

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          Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis

          Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain greatly unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high fat diet), early neutrophil infiltration and NET formation was seen, and was followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with DNase or using mice knocked-out for peptidyl arginine deaminase type IV (PAD4 −/− ), did not affect the development of a fatty liver, but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. Conclusion Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH.
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            mTORC2 Promotes Tumorigenesis via Lipid Synthesis

            Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production.
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              Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP.

              An enhanced capacity for de novo lipid synthesis is a metabolic feature of most cancer cells that distinguishes them from their cells of origin. However, the mechanisms through which oncogenes alter lipid metabolism are poorly understood. We find that expression of oncogenic PI3K (H1047R) or K-Ras (G12V) in breast epithelial cells is sufficient to induce de novo lipogenesis, and this occurs through the convergent activation of the mechanistic target of rapamycin complex 1 (mTORC1) downstream of these common oncogenes. Oncogenic stimulation of mTORC1 signaling in this isogenic setting or a panel of eight breast cancer cell lines leads to activation of the sterol regulatory element-binding proteins (SREBP1 and SREBP2) that are required for oncogene-induced lipid synthesis. The SREBPs are also required for the growth factor-independent growth and proliferation of oncogene-expressing cells. Finally, we find that elevated mTORC1 signaling is associated with increased mRNA and protein levels of canonical SREBP targets in primary human breast cancer samples. These data suggest that the mTORC1/SREBP pathway is a major mechanism through which common oncogenic signaling events induce de novo lipid synthesis to promote aberrant growth and proliferation of cancer cells.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                15 December 2019
                04 December 2019
                : 11
                : 23
                : 10839-10860
                Affiliations
                [1 ]Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
                [2 ]Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
                [3 ]Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
                [4 ]Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
                [5 ]Department of Thoracic Oncology, The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
                [6 ]Department of Interventional Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Jian Li; email: lijian5@mail.sysu.edu.cn
                Correspondence to: Chaonong Cai; email: caichn@mail.sysu.edu.cn
                Correspondence to: Hui Guo; email: guohui2@mail.sysu.edu.cn
                Article
                102488 102488
                10.18632/aging.102488
                6932893
                31796646
                b87701c7-8a4d-45c9-a543-f27193b9bbe8
                Copyright © 2019 Chen et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 February 2019
                : 17 November 2019
                Categories
                Research Paper

                Cell biology
                hepatocellular carcinoma,non-alcoholic fatty liver disease,microenvironment,hif-2α,lipid metabolism

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