Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.
Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.
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Clusterin 通过 EIF3I/Akt/MMP13 信号传导促进肝细胞癌转移
DOI：
10.18632/oncotarget.3093
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发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Qin W
中科院分区：
文献类型：
--
作者：
Wang C;Jin G;Jin H;Wang N;Luo Q;Zhang Y;Gao D;Jiang K;Gu D;Shen Q;Huo X;Hu F;Ge T;Zhao F;Chu W;Shu H;Yao M;Cong W;Qin W
聚集素(CLU)是一种应激诱导的伴侣蛋白，赋予癌细胞增殖和存活的优势。然而，CLU在肝细胞癌转移中的作用及其分子机制尚不清楚。本研究利用肝细胞癌组织芯片(n=198)研究CLU表达与临床病理特征的相关性。CLU在肝癌组织中的过度表达与较短的总生存期和较高的肿瘤复发有关。体外和体内实验表明，沉默CLU可抑制肝癌细胞的侵袭和转移，而异位过表达CLU可导致肝癌细胞的强迫转移。我们还发现，CLU通过与真核细胞翻译起始因子3亚单位I(EIF3I)络合激活Akt信号，进而促进基质金属蛋白酶13(MMP13)的表达，从而促进肝癌转移。肝细胞癌组织中CLU与MMP13、p-Akt、EIF3I呈正相关。我们进一步观察到，使用CLU抑制剂OGX-011的CLU基因敲除通过抑制EIF3I/Akt/MMP13信号，显著抑制了两种转移模型中的肝癌转移。提示CLU是肝细胞癌预后的独立预测因子，并通过EIF3I/Akt/MMP13信号通路促进肿瘤转移。使用OGX-011抑制CLU可能是抑制肝细胞癌转移的一种有前途的治疗选择。
Clusterin (CLU) is a stress-induced chaperone that confers proliferative and survival advantages to cancer cells. However, effects and molecular mechanisms of CLU in hepatocellular carcinoma (HCC) metastasis are still unknown. In this study, HCC tissue array (n = 198) was utilized to investigate correlation between CLU expression and clinicopathological features. Overexpression of CLU in HCC tissues was correlated with shorter overall survival and higher tumor recurrence. In vitro and in vivo assays demonstrated that silencing CLU attenuated the invasion and metastasis of HCC cells, whereas ectopic overexpression of CLU resulted in the forced metastasis of HCC cells. We also revealed that CLU activated Akt signaling through complexing with eukaryotic translation initiation factor 3 subunit I (EIF3I), which in turn promoted matrix metalloproteinase 13 (MMP13) expression and HCC metastasis. Positive correlations between CLU and MMP13, p-Akt, or EIF3I were found in HCC tissues. We further observed that CLU knockdown using the CLU inhibitor OGX-011 significantly suppressed HCC metastasis in two metastatic models through inhibiting EIF3I/Akt/MMP13 signaling. These findings indicate that CLU is an independent predictive factor for prognosis of HCC and it facilitates metastasis through EIF3I/Akt/MMP13 signaling. CLU suppression using OGX-011 may represent a promising therapeutic option for suppressing HCC metastasis.
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