Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model

Journal of Hematology & Oncology

Zhao-You Tang¹  Ling-Qun Kong¹  Yang Bu¹  Yuan-Yuan Zhang¹  Lu Lu¹  Xiao-Dong Zhu¹  Zong-Tao Chai¹  Jian-Yang Ao¹  Hui-Chuan Sun¹  Quan-Bao Zhang¹  Qiang-Bo Zhang²  Ke-Zhi Zhang¹ 

[1] Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 136 Yi Xue Yuan Road, Shanghai 200032, P R China;Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, P R China

关键词: GLI1;    Differentiation;    Cancer stem cell;    Hepatocellular carcinoma;    Arsenic trioxide;   

Others  :  801567
DOI  :  10.1186/1756-8722-7-28

 received in 2013-12-29, accepted in 2014-03-20,  发布年份 2014

【 摘 要 】

Background

Cancer stem cells (CSCs) play a key role in the posthepatectomy recurrence of hepatocellular carcinoma (HCC). CD133⁺ HCC cells exhibit liver CSC–like properties, and CSC differentiation–inducing therapy may lead these cells to lose their self-renewal ability and may induce terminal differentiation, which may in turn allow their malignant potential to be controlled. Because arsenic trioxide (As₂O₃) increases remission rates and prolongs survival among patients with acute promyelocytic leukemia by inducing differentiation and apoptosis of leukemic cells, we hypothesized that As₂O₃ might also inhibit HCC recurrence and prolong survival time after hepatectomy by inducing differentiation of HCC CSCs.

Methods

We evaluated the As₂O₃ induced differentiation of human HCC CSCs and its mechanism in vitro, and we investigated the effects of treatment with As₂O₃ on recurrence rates and median survival in a mouse xenograft model.

Results

We found that As₂O₃ induced HCC CSC differentiation by down-regulating the expression of CD133 and some stemness genes, thus inhibiting the cells’ self-renewal ability and tumorigenic capacity without inhibiting their proliferation in vitro. In vivo experiments indicated that As₂O₃ decreased recurrence rates after radical resection and prolonged survival in a mouse model. As₂O₃, which shows no apparent toxicity, may induce HCC CSC differentiation by down-regulating the expression of GLI1.

Conclusions

We found that As₂O₃ induced HCC CSC differentiation, inhibited recurrence, and prolonged survival after hepatectomy by targeting GLI1expression. Our results suggest that the clinical safety and utility of As₂O₃ should be further evaluated.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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