期刊
CELL AND BIOSCIENCE
卷 4, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/2045-3701-4-22
关键词
Mesenchymal stem cells; Inflammation; Autophagy; Hepatocellular carcinoma
资金
- Key Basic Research Project of China [2012CBA01303, 2011CB966200, 2010CB945600, 2011CB965100]
- Key project of National Natural Science Foundation of China [81030041]
- National Natural Science Foundation of China [31171321, 81101622, 81372330]
- Special Funds for National key Sci-Tech Sepcial Project of China [2012ZX10002-016, 2012ZX10002011-011]
- Shanghai Science and Technology Committee [11ZR1449500, 12ZR1439800]
- Shanghai Municipal Health Bureau [XYQ2011044]
- Science Fund for Creative Research Groups, NSFC, China [81221061]
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-beta 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-gamma and TNF-alpha 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-gamma plus TNF-alpha, 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-gamma and TNF-alpha provoked expression of TGF-beta by MSCs. MSCs-induced chemoresistance in HCC cell lines was correlated with the up-regulation of TGF-beta expression by MSCs. Knockdown of TGF-beta expression by MSCs with siRNA attenuated MSCs-induced chemoresistance in HCC cells. Conclusions: These results suggest that increase in TGF-beta expression by MSCs in the inflammatory microenvironment of HCC promotes the development of chemoresistance in HCC cells.
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