HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway
HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway
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DOI：
10.18632/aging.102488
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发表时间：
2019-12-15
期刊：
影响因子：
5.2
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Chen, Jianxu;Chen, Jiandi;Li, Jian
非酒精性脂肪性肝病（NAFLD）是发生肝细胞癌（HCC）的相关危险因素。脂肪性肝细胞癌（SH-HCC）以脂肪变性HCC为特征，受脂质代谢紊乱的影响。缺氧微环境在HCC中很常见，并影响脂质代谢。然而，缺氧诱导的HIF-2 α上调是否会加剧脂质积累，从而促进SH-HCC的进展尚不清楚。在这项研究中，我们证明了NAFLD-HCC患者组织中HIF-2 α升高，并与生存率相关。在缺氧条件下，HIF-2 α上调伴随着脂质积累和PI3K-AKT-mTOR通路激活。脂肪变性HCC中HIF-2 α下调（KD）可改善甘油三酯积累和脂肪变性。HIF-2 α - kd脂肪变性HCC在缺氧环境下脂质合成最少，这有助于减少恶性行为。然而，MHY1485治疗恢复了这些行为。STAM小鼠，一种发生NAFLD-HCC的小鼠模型，在暴露于缺氧时表现出更快的肿瘤进展。用INK-128处理的STAM小鼠在低氧条件下，甘油三酯和脂肪变性降低，mTOR表达和肿瘤进展完全消失。总之，在缺氧微环境下，HIF-2 α上调通过激活PI3K-AKT-mTOR途径的脂质合成来促进脂肪变性HCC的进展。因此，HIF-2 α可作为NAFLD-HCC患者特异性治疗措施的生物标志物和靶点。
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-2 alpha upregulation exacerbates lipid accumulation to contribute to SH-HCC progression remains unclear. In this study, we demonstrated that HIF-2 alpha was elevated in tissues from NAFLD-HCC patients and was associated with survival. Under hypoxic conditions, upregulated HIF-2 alpha was accompanied by lipid accumulation and PI3K-AKT-mTOR pathway activation. HIF-2 alpha knockdown (KD) in steatotic HCC ameliorated triglyceride accumulation and steatosis. HIF-2 alpha-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-2 alpha upregulation promotes steatotic HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Therefore, HIF-2 alpha can be a biomarker and target in developing specific therapeutic measures for NAFLD-HCC patients.