Journal
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Volume 30, Issue 5, Pages 925-932Publisher
WILEY
DOI: 10.1111/jgh.12873
Keywords
hepatocellular carcinoma; hypoxia; liver fibrosis; transarterial chemoembolization
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Funding
- National Natural Science Foundation of China [81071896, 81270505]
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Background and AimIt 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. MethodsSerum 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 (-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. ResultsPatients 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 -SMA staining, as well as increased expression of hypoxia-inducible factor (HIF)-1, transforming growth factor (TGF)-1, and vascular endothelial growth factor (VEGF). Conditioned media of hypoxia-treated L02 cells induced the expression of Collagen I and -SMA in LX-2 cells, which was inhibited by HIF-1 small interfering RNA. Finally, HIF-1 inhibitor LW6 attenuated the hypoxia-induced fibrosis progression in vivo. ConclusionOur 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-1 might be a valuable strategy to optimize the efficacy and reduce the complication of TACE.
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