Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma

Guofeng Yu; Yingying Jing; Xingrui Kou; Fei Ye; Lu Gao; Qingmin Fan; Yang Yang; Qiudong Zhao; Rong Li; Mengchao Wu; Lixin Wei

doi:10.1371/journal.pone.0073312

Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma

PLoS One. 2013 Sep 2;8(9):e73312. doi: 10.1371/journal.pone.0073312. eCollection 2013.

Authors

Guofeng Yu¹, Yingying Jing, Xingrui Kou, Fei Ye, Lu Gao, Qingmin Fan, Yang Yang, Qiudong Zhao, Rong Li, Mengchao Wu, Lixin Wei

Affiliation

¹ Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China ; Soochow University, Suzhou, Jiangsu, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cisplatin / pharmacology
Culture Media / metabolism
Drug Resistance, Neoplasm*
Epithelial-Mesenchymal Transition / drug effects
Hepatic Stellate Cells / drug effects
Hepatic Stellate Cells / metabolism*
Hepatic Stellate Cells / pathology
Hepatocyte Growth Factor / deficiency
Hepatocyte Growth Factor / metabolism*
Humans
Liver Neoplasms / metabolism
Liver Neoplasms / pathology*
Male
Mice
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / pathology
Phenotype

Substances

Culture Media
Hepatocyte Growth Factor
Cisplatin

Grants and funding

Key Basic Research Project of China (Grant NO. 2012CBA01303, 2011CB966200, 2010CB945600, 2011CB965100); Key project of National Natural Science Foundation of China(Grant NO. 81030041); National Natural Science Foundation of China (Grant NO. 31171321, 81101622?81201584); Special Funds for National key Sci-Tech Special Project of China (Grant NO. 2012ZX10002-016, 2012ZX10002011-011); Shanghai Science and Technology Committee (Grant NO. 11ZR1449500, 12ZR1454200, 12ZR1439800, 11nm0504700); Shanghai Municipal Health Bureau (Grant NO. XYQ2011044, 20114004) and Science Fund for Creative Research Groups, NSFC, China (Grant NO. 81221061). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.