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

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 (As&sub2;O&sub3;) increases remission rates and prolongs survival among patients with acute promyelocytic leukemia by inducing differentiation and apoptosis of leukemic cells, we hypothesized that As&sub2;O&sub3; might also inhibit HCC recurrence and prolong survival time after hepatectomy by inducing differentiation of HCC CSCs.

We found that As&sub2;O&sub3; induced HCC CSC differentiation, inhibited recurrence, and prolonged survival after hepatectomy by targeting GLI1expression. Our results suggest that the clinical safety and utility of As&sub2;O&sub3; should be further evaluated.

We evaluated the As&sub2;O&sub3; induced differentiation of human HCC CSCs and its mechanism in vitro, and we investigated the effects of treatment with As&sub2;O&sub3; on recurrence rates and median survival in a mouse xenograft model.

We found that As&sub2;O&sub3; 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 As&sub2;O&sub3; decreased recurrence rates after radical resection and prolonged survival in a mouse model. As&sub2;O&sub3;, which shows no apparent toxicity, may induce HCC CSC differentiation by down-regulating the expression of GLI1. Conclusions: We found that As&sub2;O&sub3; induced HCC CSC differentiation, inhibited recurrence, and prolonged survival after hepatectomy by targeting GLI1expression. Our results suggest that the clinical safety and utility of As&sub2;O&sub3; should be further evaluated.