Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.

Cun Wang,Wenming Cong,Guangzhi Jin,Xisong Huo,Tianxiang Ge,Kai Jiang,Qin Luo,Wenxin Qin,Fangyu Zhao,Huiqun Shu,Qiujing Shen,Ning Wang,Fangyuan Hu,Ming Yao,Dongmei Gao,Wei Chu,Dishui Gu,Haojie Jin,Yurong Zhang

doi:10.18632/oncotarget.3093

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third leading cause of cancerrelated death worldwide[1, 2]
We presented the first evidence that CLU, as a functional homolog of heat-shock proteins (Hsps), was closely associated with poor prognosis of HCC patients
A positive correlation between expression level of CLU and early HCC recurrence was found and suggested that cancer cells with high expression of CLU have more invasive phenotype (Figure 1). These results indicated that CLU might be a prospective prognostic marker for HCC patients

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third leading cause of cancerrelated death worldwide[1, 2]. Various proteins and signaling pathways have been found to closely correlate with the recurrence and metastasis of HCC patients[5]. Molecular chaperones www.impactjournals.com/oncotarget assist cells deal with cellular stresses-induced protein misfolding, aggregation, and denaturation. They play critical roles in cell survival, cell migration, cell adhesion, transformation, and cell-cell interactions[6]. Because of the existence of ischemic and hypoxic microenvironment in cancer tissues, various kinds of molecular chaperones including heat shock protein 27 (Hsp 27)[7], Hsp90[8, 9], αB-crystallin[10], and clusterin (CLU)[11,12,13,14] are often adaptively overexpressed and closely related with the increased tumorigenicity, metastatic potential, and resistance to chemotherapy

Methods

Results

Conclusion