title: Mesenchymal stem cells contribute to the chemoresistance of hepatocellular carcinoma cells in inflammatory environment by inducing autophagy.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) have been reported to play an important role in tumor growth. Inflammation is an important feature of hepatocellular carcinoma (HCC). Certain inflammatory cytokines produced in tumor microenvironment modulate functional activities of MSCs. At the present time, however, the role of MSCs in the development of HCC cell resistance to chemotherapy in the inflammatory microenvironment during tumor growth has not yet been identified.
  
  
  METHODS
  MTT and PI/Annexin V-FITC assay were employed to examine the proliferation and apoptosis of HCC cell lines. The expression of TGF-β are detected by Realtime PCR and Western blot. GFP tagged LC3 expression vector and electron microscopy are utilized to demonstrate the occurrence of autophagy.
  
  
  RESULTS
  We observed that MSCs pretreated with the combination of IFN-γ and TNF-α induced resistance to chemotherapy in HCC cell lines in both the in vitro and in vivo circumstances. Following exposure to conditioned medium of MSCs that were pre-treated with IFN-γ plus TNF-α, HCC cell line cells underwent autophagy which serves as a protective mechanism for HCC cells to resist the cell toxicity of chemotherapeutic agents. Treatment of HCC cell line cells with autophagy inhibitor effectively reversed the MSCs-induced resistance to chemotherapy in these cells. Stimulation with the combination of IFN-γ and TNF-α provoked expression of TGF-β by MSCs. MSCs-induced chemoresistance in HCC cell lines was correlated with the up-regulation of TGF-β expression by MSCs. Knockdown of TGF-β expression by MSCs with siRNA attenuated MSCs-induced chemoresistance in HCC cells.
  
  
  CONCLUSIONS
  These results suggest that increase in TGF-β expression by MSCs in the inflammatory microenvironment of HCC promotes the development of chemoresistance in HCC cells.
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Han
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Comprehensive Treatment, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Radiation Oncology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Gastroenterology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: Fenghai
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital and Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medicial University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wei
keywords: Autophagy; Hepatocellular carcinoma; Inflammation; Mesenchymal stem cells