title: Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.
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.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Haojie
authors.initials: H
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Gao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Dishui
authors.initials: D
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xisong
authors.initials: X
authors.lastname: Huo
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Huiqun
authors.initials: H
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Cong
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000628:therapy; D002465:Cell Movement; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D039621:Eukaryotic Initiation Factor-3; C503781:OGX-011; D013873:Thionucleotides; C096013:EIF3I protein, human; D051057:Proto-Oncogene Proteins c-akt; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13