25^th World Cancer Conference

Nitroso-compounds are critical dietary risk factor of liver cancer. Cancer stem cells (CSCs) play a significant role in the formation and development of cancer. To date, the action of nitroso-compounds on the induction of liver CSCs as well as the underlying mechanisms has not been defined. In the present study, we revealed that chronic N-nitroso dimethylamine (NDMA) exposure induced malignant transformation of human normal liver cells. We further showed that NDMA-induced malignant transformed liver cells exhibited CSCs properties, as evidenced by increased sphere formation capacity in serumfree- medium culture, dramatically elevated expression of liver CSCs markers and increased number of CD133+ cells, along with upregulation of TAp63α, downregulation of ΔNp63α, and activation of Sonic Hedgehog pathway. Moreover, we illustrated that suppression of Sonic Hedgehog activity inhibited NDMA-induced liver CSCs properties; over expression of TAp63α activated Sonic Hedgehog pathway and promoted liver CSCs activity, whereas down expression of TAp63α inhibited Sonic Hedgehog and suppressed liver CSCs; an opposite action of ΔNp63α on Sonic Hedgehog pathway and liver CSCs was demonstrated. Taken together, our data suggested for the first time the vital role of TP63α/Sonic Hedgehog axis in regulating NDMA-induced liver CSCs, and thus could provide new insights into the molecular mechanisms of liver carcinogenesis as well as its target intervention.