Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2 drives metastasis of hepatocellular carcinoma

Oxidative stress and hypoxia are two opposite microenvironments involved in HCC metastasis. Thioredoxin (TXN) and hypoxia-inducible factor 2 alpha (HIF-2 alpha) are typical proteins involved in these two different microenvironments, respectively. How these two factors interact to influence the fate on tumor cells remains unknown. Hypoxia facilitated HCC cells withstood oxidative stress and eventually promoted HCC cells metastasis, in which TXN and HIF-2 alpha were mostly involved. Upregulation of TXN/HIF-2 alpha correlated with poor HCC prognosis and promoted HCC metastasis both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) process was involved in TXN/HIF-2 alpha -enhanced invasiveness of HCC cells. Additionally, the stability and activity of HIF-2 alpha were precisely regulated by TXN via SUMOylation and acetylation, which contributed to HCC metastasis. Our data revealed that the redox protein TXN and HIF-2 alpha are both associated with HCC metastasis, and the fine regulation of TXN on HIF-2 alpha contributes essentially during the process of metastasis. Our study provides new insight into the interaction mechanism between hypoxia and oxidative stress and implies potential therapeutic benefits by targeting both TXN and HIF-2 alpha in the treatment of HCC metastasis.