title: Activated hepatic stellate cells promote hepatocellular carcinoma cell migration and invasion via the activation of FAK-MMP9 signaling.
abstract: Activated hepatic stellate cells (HSCs) are the major subtype of stromal cells in the liver tumor microenvironment which can promote the growth and migration of hepatocellular carcinoma (HCC) cells. However, the underlying mechanisms by which activated HSCs exert their oncogenic effects are not fully understood to date. In the present study, we investigated the number of activated HSCs and its clinicopathological significance in HCC and uncovered its correlation with focal adhesion kinase (FAK)-MMP9 signaling. A higher number of activated HSCs was associated with tumor invasion of the portal vein, advanced TNM stage and poorer tumor differentiation. The number of activated HSCs was positively correlated with the expression levels of p-FAK and MMP9 in HCC. Furthermore, we studied the effects of activated HSCs on the migration and invasion of HCC cells in vitro. Conditioned medium (CM) from activated HSCs or co-culture with activated HSCs significantly induced the migration and invasion of HCC cells. In addition, activation of FAK-MMP9 signaling in HCC was demonstrated in the presence of activated HSC-CM and of co-culture. Inhibition of FAK-MMP9 signaling in HCC cells with FAK short hairpin RNA (shRNA) abrogated the effects of activated HSCs on HCC cells. Taken together, our data suggest that activated HSCs in the tumor microenvironment promote HCC cell migration and invasion via activation of FAK-MMP9 signaling.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
authors.forename: Shaoshan
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Immunology and Pathogenic Biology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zan
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
authors.forename: Qingguang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D034741:RNA, Small Interfering; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9