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Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma.

Authors :
Zheng Wang
Jian Zhou
Jia Fan
Chang-Jun Tan
Shuang-Jian Qiu
Yao Yu
Xiao-Wu Huang
Zhao-You Tang
Source :
Journal of Cancer Research & Clinical Oncology. May2009, Vol. 135 Issue 5, p715-722. 8p. 1 Color Photograph, 2 Charts, 6 Graphs.
Publication Year :
2009

Abstract

Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC. MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression. In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia. The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
01715216
Volume :
135
Issue :
5
Database :
Academic Search Index
Journal :
Journal of Cancer Research & Clinical Oncology
Publication Type :
Academic Journal
Accession number :
37226245
Full Text :
https://doi.org/10.1007/s00432-008-0506-z