Transarterial chemoembolization aggravated peritumoral fibrosis via hypoxia-inducible factor-1α dependent pathway in hepatocellular carcinoma

• Published in: Journal of gastroenterology and hepatology 2015-05, Vol.30 (5), p.925-932
• Main Authors: Qu, Kai, Yan, Zhaoyong, Wu, Yousheng, Chen, Yibing, Qu, Ping, Xu, Xinsen, Yuan, Peng, Huang, Xiaojun, Xing, Jinliang, Zhang, Hongxin, Liu, Chang, Zhang, Jing
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell Hypoxia; Chemoembolization, Therapeutic - adverse effects; Disease Models, Animal; Disease Progression; Epirubicin - administration & dosage; Epirubicin - adverse effects; Female; Fibrosis; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; hepatocellular carcinoma; Humans; hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Infusions, Intra-Arterial; Liver - pathology; Liver Cirrhosis, Experimental; liver fibrosis; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Male; Middle Aged; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Rats, Sprague-Dawley; transarterial chemoembolization
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.12873

Background and Aim It was commonly accepted that chemotherapeutic cytotoxicity was the main cause for hepatic failure in hepatocellular carcinoma patients after repeated transarterial chemoembolization (TACE). However, the effect of embolization‐induced hypoxia on liver cirrhosis has rarely been concerned. Methods Serum levels of alanine aminotransferase, aspartate aminotransferase, and albumin were used to detect liver injury. Hepatic artery ligation was performed in carbon tetrachloride‐induced rat hepatic fibrosis model to mimic the effect of hepatic hypoxia on liver fibrosis after TACE. Sirius Red staining and immunohistochemical analysis of alpha‐smooth muscle actin (α‐SMA) were used to detect the activation of hepatic stellate cells. Moreover, the expression of hypoxia and fibrosis‐related molecules were analyzed at protein and/or mRNA level. Results Patients showed a significant increase in alanine aminotransferase and aspartate aminotransferase (P = 0.006), accompanied by a decrease in albumin (P = 0.005) after repeated TACE. Hepatic artery ligation significantly promoted carbon tetrachloride‐induced rat liver fibrosis progression as indicated by Sirius Red and α‐SMA staining, as well as increased expression of hypoxia‐inducible factor (HIF)‐1α, transforming growth factor (TGF)‐β1, and vascular endothelial growth factor (VEGF). Conditioned media of hypoxia‐treated L02 cells induced the expression of Collagen I and α‐SMA in LX‐2 cells, which was inhibited by HIF‐1α small interfering RNA. Finally, HIF‐1α inhibitor LW6 attenuated the hypoxia‐induced fibrosis progression in vivo. Conclusion Our data demonstrate that TACE‐induced hepatic hypoxia aggravates the fibrosis progression in peritumoral liver tissue, thus leads to the deterioration of liver function. Intervention of HIF‐1α might be a valuable strategy to optimize the efficacy and reduce the complication of TACE.