HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma.
HK1 from hepatic stellate cell-derived extracellular vesicles promotes progression of hepatocellular carcinoma.
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肝星状细胞来源的细胞外囊泡中的 HK1 促进肝细胞癌的进展
DOI：
10.1038/s42255-022-00642-5
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发表时间：
2022-10
影响因子：
20.8
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Chen, Qi-tao;Zhang, Zhi-yuan;Huang, Qiao-ling;Chen, Hang-zi;Hong, Wen-bin;Lin, Tianwei;Zhao, Wen-xiu;Wang, Xiao-min;Ju, Cui-yu;Wu, Liu-zheng;Huang, Ya-ying;Hou, Pei-pei;Wang, Wei-jia;Zhou, Dawang;Deng, Xianming;Wu, Qiao
细胞外囊泡在肿瘤微环境中的细胞间通讯中起着至关重要的作用。在这里，我们证明了在肝纤维化中，TGF-β刺激肝星状细胞（HSC）中己糖激酶1（HK 1）的棕榈酰化，这有助于HK 1以TSG 101依赖性方式通过大的细胞外囊泡分泌。大的细胞外囊泡HK 1被肝细胞癌（HCC）细胞劫持，导致糖酵解加速和HCC进展。在HSC中，核受体Nur 77转录激活脱棕榈酰酶ABHD 17 B的表达以抑制HK 1棕榈酰化，从而减弱HK 1释放。然而，TGF-β激活的Akt通过诱导Nur 77磷酸化和降解而功能性地抑制Nur 77。我们鉴定了结合Nur 77以产生空间位阻来阻断Akt靶向的小分子PDNPA，从而破坏Akt介导的Nur 77降解并保持Nur 77对HK 1释放的抑制。总之，这项研究证明了HK 1从HSC释放后在HCC中被忽视的功能，并强调PDNPA作为抑制HCC进展的候选化合物。己糖激酶1被发现响应于TGF-β从肝星状细胞分泌到大的细胞外囊泡中，并且随后被肝细胞癌细胞摄取，在那里它促进肿瘤进展和转移。
Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-β stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-β-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression. Hexokinase 1 is found to be secreted from hepatic stellate cells in large extracellular vesicles in response to TGF-β, and is subsequently taken up by hepatocellular carcinoma cells, where it promotes tumor progression and metastasis.
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