Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma
Metrics: PDF 3091 views | HTML 3497 views | ?
Cun Wang1,*, Guangzhi Jin2,*, Haojie Jin1,*, Ning Wang1, Qin Luo1, Yurong Zhang1, Dongmei Gao3, Kai Jiang3, Dishui Gu1, Qiujing Shen1, Xisong Huo1, Fangyuan Hu1, Tianxiang Ge1, Fangyu Zhao1, Wei Chu1, Huiqun Shu1, Ming Yao1, Wenming Cong2 and Wenxin Qin1
1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
3 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
* These authors contributed equally to this work
Wenxin Qin, email:
Wenming Cong, email:
Keywords: Clusterin, hepatocellular carcinoma, metastasis, prognosis, OGX-011
Received: November 16, 2014 Accepted: December 25, 2014 Published: December 30, 2014
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.