The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells
The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells
复制标题
癌蛋白 HBXIP 通过调节 PCK1 抑制糖异生，促进肝癌细胞生长
DOI：
10.1016/j.canlet.2016.08.025
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发表时间：
2016-11-28
期刊：
影响因子：
9.7
通讯作者：
Ye, Lihong
中科院分区：
文献类型：
--
作者：
Shi, Hui;Fang, Runping;Ye, Lihong
乙肝X-相互作用蛋白(HBXIP)作为一种癌蛋白，在肿瘤的发生发展过程中起着至关重要的作用，涉及糖代谢重编程。在这项研究中，我们感兴趣的是癌蛋白HBXIP是否参与了肝癌中糖异生的调节。在此，我们发现临床肝细胞癌组织中糖异生的关键酶--磷酸烯醇式丙酮酸羧激酶(PCK1)的表达水平低于正常肝组织。机制上，HBXIP通过下调肝癌细胞转录因子FOXO1抑制PCK1的表达，上调针对FOXO1基因3‘端非编码区的miR-135a。此外，HBXIP通过激活PI3K/Akt通路增加FOXO1蛋白的磷酸化水平，导致FOXO1从细胞核输出到细胞质。值得注意的是，PCK1的过表达可以取消HBXIP促进的肝癌细胞在体内外的生长。因此，我们认为HBXIP蛋白可能通过抑制PCK1促进肝癌的发生而抑制糖异生，参与miR-135a/FOXO1轴和PI3K/AkTIP-FOXO1途径。我们的发现为癌蛋白HBXIP调节肝细胞癌葡萄糖代谢重编程的机制提供了新的见解。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Hepatitis B X-interacting protein (HBXIP) as an oncoprotein plays crucial roles in the development of cancer, involving glucose metabolism reprogramming. In this study, we are interested in whether the oncoprotein HBXIP is involved in the modulation of gluconeogenesis in liver cancer. Here, we showed that the expression level of phosphoenolpyruvate carboxykinase (PCK1), a key enzyme of gluconeogenesis, was lower in clinical hepatocellular carcinoma (HCC) tissues than that in normal tissues. Mechanistically, HBXIP inhibited the expression of PCK1 through down-regulating transcription factor FOXO1 in hepatoma cells, and up-regulated miR-135a targeting the 3'UTR of FOXO1 mRNA in the cells. In addition, HBXIP increased the phosphorylation levels of FOXO1 protein by activating PI3K/Akt pathway, leading to the export of FOXO1 from nucleus to cytoplasm. Strikingly, over-expression of PCK1 could abolish the HBXIP-promoted growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP is able to depress the gluconeogenesis through suppressing PCK1 to promote hepatocarcinogenesis, involving miR-135a/FOXO1 axis and PI3K/Aktip-FOXO1 pathway. Our finding provides new insights into the mechanism by which oncoprotein HBXIP modulates glucose metabolism reprogramming in HCC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.