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

Ke-Zhi Zhang,Quan-Bao Zhang,Lu Lu,Yang Bu,Hui-Chuan Sun,Yuan-Yuan Zhang,Xiao-Dong Zhu,Zong-Tao Chai,Jian-Yang Ao,Ling-Qun Kong,Zhao-You Tang,Qiang-Bo Zhang

doi:10.1186/1756-8722-7-28

Abstract

BackgroundCancer 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Highlights

Cancer stem cells (CSCs) play a key role in the posthepatectomy recurrence of hepatocellular carcinoma (HCC)
Two studies have reported that hepatocyte nuclear factor 4 alpha and bone morphogenetic protein 4 can promote the differentiation of CD133+ HCC stem cells, inhibition of self-renewal, and resistance to chemotherapy [18,19]; and these results suggest that inducing CSC differentiation is a promising approach to the treatment of HCC
To determine whether As2O3 inhibited proliferation of CD133+ HCC cells, we performed a CCK8 cell proliferation assay, the results of which showed that As2O3 had little effect on CD133+ cell proliferation at 1–4 μM (Figure 1E)

Summary

Introduction

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. CSCs have the ability to self-renew, to differentiate into defined progeny, and, most importantly, to initiate and sustain tumor growth, and they play a key role in tumor progression, metastasis, and recurrence [7]. Two studies have reported that hepatocyte nuclear factor 4 alpha and bone morphogenetic protein 4 can promote the differentiation of CD133+ HCC stem cells, inhibition of self-renewal, and resistance to chemotherapy [18,19]; and these results suggest that inducing CSC differentiation is a promising approach to the treatment of HCC. The use of differentiation-inducing drugs for HCC has not been well explored

Methods

Results

Conclusion