title: Tumor-derived secretory clusterin induces epithelial-mesenchymal transition and facilitates hepatocellular carcinoma metastasis.
abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Metastasis is the major concern that causes death in HCC. The goal of this study was to identify tumor-derived proteins in serum during HCC metastasis using an orthotopic xenograft tumor model and explore the role of key protein in HCC metastasis. Serum samples collected from HCCLM3-R metastatic HCC tumor model at specific stages of metastasis (1 wk, 3 wks and 6 wks) were subjected to iTRAQ labeling followed by 2DLC-ESI-MS/MS analysis. Twenty tumor-derived proteins were identified through human specific peptides. Secretory clusterin (sCLU), which was significantly upregulated during cancer progression and metastasis, was chosen for further study. The expression of sCLU was significantly higher in metastatic HCC cell lines and samples from metastatic HCC patients. ShRNA-mediated down-regulation of sCLU resulted in a reduced migratory capacity in HCC cell lines, as well as a reduction in pulmonary metastasis in vivo. Overexpression of sCLU in HepG2 cell line showed increased cell migratory ability. Further study found that sCLU contributed to HCC migration and epithelial-mesenchymal transition (EMT) in vitro, and metastasis in vivo. In addition, sCLU also plays an important role in the regulation of TGF-β1-smad3 signaling. These findings suggest that sCLU may promote HCC metastasis via the induction of EMT process and may be a candidate target for HCC therapy.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Kang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Gao
authors.forename: Chun
authors.initials: C
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Liu
authors.forename: Weizhong
authors.initials: W
authors.lastname: Wu
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.forename: Kun
authors.initials: K
authors.lastname: Guo
authors.forename: Yinkun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D051152:Clusterin / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000097:blood / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D047368:Tumor Burden
chemical_list: C495242:CLU protein, human; D015820:Cadherins; D051152:Clusterin; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1