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

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 (As(2)O(3)) increases remission rates and prolongs survival among patients with acute promyelocytic leukemia by inducing differentiation and apoptosis of leukemic cells, we hypothesized that As(2)O(3) might also inhibit HCC recurrence and prolong survival time after hepatectomy by inducing differentiation of HCC CSCs. METHODS: We evaluated the As(2)O(3) induced differentiation of human HCC CSCs and its mechanism in vitro, and we investigated the effects of treatment with As(2)O(3) on recurrence rates and median survival in a mouse xenograft model. RESULTS: We found that As(2)O(3) 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(2)O(3) decreased recurrence rates after radical resection and prolonged survival in a mouse model. As(2)O(3), which shows no apparent toxicity, may induce HCC CSC differentiation by down-regulating the expression of GLI1. CONCLUSIONS: We found that As(2)O(3) 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(2)O(3) should be further evaluated.