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Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma

  • Zheng Wang
  • Jian Zhou
  • Jia FanEmail author
  • Chang-Jun Tan
  • Shuang-Jian Qiu
  • Yao Yu
  • Xiao-Wu Huang
  • Zhao-You Tang
Original Paper

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Sirolimus Hepatocellular carcinoma Liver transplantation VEGF HIF-1 a protein Immunosuppression Neoplasm metastasis 

Abbreviations

HCC

Hepatocellular carcinoma

LT

Liver transplantation

CNI

Calcineurin inhibitor

MVD

Microvessel density

Notes

Acknowledgments

The research was supported by grants from the Hi-tech Research and Development Program of China (2007AA02Z479), and the National Natural Science Foundation Grant of China (30700815).

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Zheng Wang
    • 1
  • Jian Zhou
    • 1
  • Jia Fan
    • 1
    Email author
  • Chang-Jun Tan
    • 1
  • Shuang-Jian Qiu
    • 1
  • Yao Yu
    • 1
  • Xiao-Wu Huang
    • 1
  • Zhao-You Tang
    • 1
  1. 1.Liver Cancer Institute, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China

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