Hsp90 Inhibitor STA9090 induced VPS35 related extracellular vesicle release and metastasis in hepatocellular carcinoma.
Hsp90 Inhibitor STA9090 induced VPS35 related extracellular vesicle release and metastasis in hepatocellular carcinoma.
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DOI：
10.1016/j.tranon.2022.101502
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发表时间：
2022-12
影响因子：
5
通讯作者：
Chen, Xuemei
中科院分区：
文献类型：
--
作者：
Tan, Wenchong;Zhang, Jinxin;Liu, Lixia;Liang, Manfeng;Li, Jieyou;Deng, Zihao;Zheng, Zhenming;Deng, Yaotang;Liu, Chenyang;Li, Yan;Xie, Guantai;Zhang, Jiajie;Zou, Fei;Chen, Xuemei
关键词：
VPS 35参与了N端Hsp 90抑制剂STA 9090诱导的EV形成、递送和分泌过程，但不参与C端Hsp 90抑制剂NB诱导的EV形成、递送和分泌过程，并促进HCC侵袭。Bclaf 1通过bZIP DNA结合域上调VPS 35的转录，VPS 35和Bclaf 1水平上调与HCC的不良预后和转移呈正相关。HSF 1与Bclaf 1水平呈正相关。Hsp 90抑制剂STA 9090通过HSF 1-Bclaf 1-VPS 35-EVs轴促进肝癌细胞的侵袭和转移。Bclaf 1下调可抑制Hsp 90抑制剂STA 9090诱导VPS 35相关的细胞外囊泡释放和侵袭。热休克蛋白90（Heat shock protein 90，Hsp 90）是肿瘤治疗的重要靶点。出乎意料的是，N-末端Hsp 90抑制剂STA 9090相关临床试验的单一疗法在III期停止，并且在用N-末端Hsp 90抑制剂治疗的动物模型中报告了转移。细胞内蛋白分选相关蛋白35（VPS 35）在神经退行性疾病中的内体源性EV（extracellular vesicle）运输中起着重要作用，但迄今为止还没有VPS 35相关EV在肿瘤中的报道。鉴于肿瘤源性EV有助于转移，而VPS 35最近被发现参与了肝细胞癌（HCC）的侵袭和转移，本研究探讨了N端Hsp 90抑制剂STA 9090是否诱导EV的产生以及VPS 35在其中的作用。我们发现，N端Hsp 90抑制剂STA 9090上调Bclaf 1和VPS 35的水平，增加EV的分泌，并且STA 9090诱导的EV促进HepG 2细胞的侵袭。由于临床资料提示Bclaf 1和VPS 35水平升高与HCC转移增加和预后不良相关，我们将重点放在Bclaf 1-VPS 35-EVs轴上，以进一步探讨VPS 35相关转移的机制。结果表明，Bclaf 1通过bZIP结构域促进VPS 35的转录，并且Bclaf 1或VPS 35的敲低降低了STA 9090诱导的EV的促转移能力。以上结果揭示了Bclaf 1-VPS 35-EVs轴在肝癌转移中的作用，VPS 35基因敲低可减少Hsp 90抑制剂STA 9090诱导的细胞外囊泡释放和转移，为抑制N端Hsp 90抑制剂诱导的细胞外囊泡引起的肝癌转移提供了一种新的联合治疗策略。
VPS35 involved in the EVs formation, delivery and secretion process induced by N-terminal Hsp90 inhibitor STA9090 but not C-terminal Hsp90 inhibitor NB and promoted HCC invasion. Bclaf1 upregulated VPS35 transcription through bZIP DNA binding domain, and upregulation of VPS35 and Bclaf1 levels positively correlates with poorer prognosis and metastasis in HCC. HSF1 positively correlated with Bclaf1 levels. Hsp90 inhibitor STA9090 induced EVs promote invasion and metastasis by HSF1-Bclaf1-VPS35-EVs axis in hepatocellular carcinoma. Bclaf1 down-regulation alleviates Hsp90 inhibitor STA9090 induced VPS35 related extracellular vesicle release and invasion. Heat shock protein 90 (Hsp90) has been an important therapeutic target for cancer therapy for decades. Unexpectedly, the monotherapy of N-terminal Hsp90 inhibitor STA9090 related clinical trials halted in phase III, and metastases were reported in animal models with the treatment of N-terminal Hsp90 inhibitors. Vacuolar protein sorting-associated protein 35 (VPS35) plays a vital role in endosome-derived EV (extracellular vesicle) traffic in neurodegeneration diseases, but no vps35 related EV were reported in tumors till now. Since tumor derived EVs contributes to metastasis and VPS35 is recently found to be involved in the invasion and metastasis of hepatocellular carcinoma (HCC), whether N-terminal Hsp90 inhibitor STA9090 induced EVs generation and the role of VPS35 in it were explored in this study. We found that N-terminal Hsp90 inhibitor STA9090 upregulated Bclaf1 and VPS35 levels, increased the secretion of EVs, and STA9090-induced-EVs promoted the invasion of HepG2 cells. As the clinical data suggested that the increased Bclaf1 and VPS35 levels correlated with increased metastasis and poorer prognosis in HCC, we focused on the Bclaf1-VPS35-EVs axis to further explore the mechanism of VPS35-related metastasis. The results demonstrated that Bclaf1 facilitated the transcription of VPS35 via bZIP domain, and knockdown of Bclaf1 or VPS35 alleviated pro-metastatic capability of STA9090-induced-EVs. All the results revealed the role of Bclaf1-VPS35-EVs axis on metastasis of HCC, and VPS35 knockdown decreased Hsp90 Inhibitor STA9090 induced extracellular vesicle release and metastasis, which provided a new combination therapeutic strategy to inhibit the metastasis of HCC caused by N-terminal Hsp90 inhibitor induced extracellular vesicles.
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DOI：
10.1186/bcr1996
发表时间：
2008
期刊：
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影响因子：
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影响因子：
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作者：
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