Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma.
OBJECTIVE
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.
Wang
Zheng
Z
Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, People's Republic of China.
Zhou
Jian
J
Fan
Jia
J
Tan
Chang-Jun
CJ
Qiu
Shuang-Jian
SJ
Yu
Yao
Y
Huang
Xiao-Wu
XW
Tang
Zhao-You
ZY
D000199:Actins / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000199:Actins; D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020123:Sirolimus