title: Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma.
abstract: As the main source of extracellular matrix proteins in tumor stroma, hepatic stellate cells (HSCs) have a great impact on biological behaviors of hepatocellular carcinoma (HCC). In the present study, we have investigated a mechanism whereby HSCs modulate the chemoresistance of hepatoma cells. We used human HSC line lx-2 and chemotherapeutic agent cisplatin to investigate their effects on human HCC cell line Hep3B. The results showed that cisplatin resistance in Hep3B cells was enhanced with LX-2 CM (cultured medium) exposure in vitro as well as co-injection with LX-2 cells in null mice. Meanwhile, in presence of LX-2 CM, Hep3B cells underwent epithelial to mesenchymal transition (EMT) and upregulation of cancer stem cell (CSC) -like properties. Besides, LX-2 cells synthesized and secreted hepatic growth factor (HGF) into the CM. HGF receptor tyrosine kinase mesenchymal-epithelial transition factor (Met) was activated in Hep3B cells after LX-2 CM exposure. The HGF level of LX-2 CM could be effectively reduced by using HGF neutralizing antibody. Furthermore, depletion of HGF in LX-2 CM abolished its effects on activation of Met as well as promotion of the EMT, CSC-like features and cisplatin resistance in Hep3B cells. Collectively, secreting HGF into tumor milieu, HSCs may decrease hepatoma cells sensitization to chemotherapeutic agents by promoting EMT and CSC-like features via HGF/Met signaling.
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China ; Soochow University, Suzhou, Jiangsu, China.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Yu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Jing
authors.forename: Xingrui
authors.initials: X
authors.lastname: Kou
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Fan
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Qiudong
authors.initials: Q
authors.lastname: Zhao
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Lixin
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003470:Culture Media / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010641:Phenotype
chemical_list: D003470:Culture Media; D017228:Hepatocyte Growth Factor; D002945:Cisplatin
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