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

• Published in: The FASEB journal Vol. 34; no. 4; pp. 5892 - 5905
• Main Authors: Cao, Man‐Qing, You, A‐Bin, Cui, Wei, Zhang, Su, Guo, Zhi‐Gui, Chen, Lu, Zhu, Xiao‐Dong, Zhang, Wei, Zhu, Xiao‐Lin, Guo, Hua, Deng, Da‐Jun, Sun, Hui‐Chuan, Zhang, Ti
• Format: Journal Article
• Language: English
• Published: United States 01-04-2020
• Subjects: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; hepatocellular carcinoma; HIF‐2α; Humans; Hypoxia - physiopathology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Oxidative Stress; Prognosis; thioredoxin; Thioredoxins - genetics; Thioredoxins - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; HIF-2α; metastasis; thioredoxin; hepatocellular carcinoma
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202000082R

Oxidative stress and hypoxia are two opposite microenvironments involved in HCC metastasis. Thioredoxin (TXN) and hypoxia‐inducible factor 2α (HIF‐2α) 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‐2α were mostly involved. Upregulation of TXN/HIF‐2α 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‐2α‐enhanced invasiveness of HCC cells. Additionally, the stability and activity of HIF‐2α were precisely regulated by TXN via SUMOylation and acetylation, which contributed to HCC metastasis. Our data revealed that the redox protein TXN and HIF‐2α are both associated with HCC metastasis, and the fine regulation of TXN on HIF‐2α 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‐2α in the treatment of HCC metastasis.