HEPATOLOGY Transarterial chemoembolization aggravated peritumoral fibrosis via hypoxia-inducible factor-1α dependent pathway in hepatocellular carcinoma Kai Qu,* ,1 Zhaoyong Yan, †,1 Yousheng Wu, ‡,1 Yibing Chen, ‡ Ping Qu, ‡ Xinsen Xu,* Peng Yuan, † Xiaojun Huang, ‡ Jinliang Xing, ‡ Hongxin Zhang, † Chang Liu* and Jing Zhang ‡ *Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, † Department of Pain Treatment, Tangdu Hospital, and ‡ State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China Key words hepatocellular carcinoma, hypoxia, liver fibrosis, transarterial chemoembolization. Accepted for publication 9 December 2014. Correspondences Dr Jing Zhang, State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University; 169 Changle West Road, Xi’an 710032, China. Email: zhanglu1@fmmu.edu.cn Chang Liu, Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, 277 Yanta West Road, Xi’an 710061, China. Email: liuchangdoctor@163.com Hongxin Zhang, Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University; 1 Xinsi Road, Xi’an 710038, China. Email: zhhxtdjr@163.com 1 Kai Qu, Zhaoyong Yan and Yousheng Wu contributed equally to this work. Declaration of conflict of interest: The authors declare that they have no conflicts of interest. Abstract 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. Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide. 1 Currently, surgical resection is the primary curative therapy for HCC patient. However, minority of patients are eli- gible for resection because of limitation of operation indications. Most of HCC patients were diagnosed in the late and symptomatic stage, where therapeutic options are limited. 2 In patients who are unsuitable candidates for surgery, embolization or transarterial chemoembolization (TACE) provides an attractive palliative thera- peutic choice for disease control and survival prolongation. 3,4 Emerging at the late 1970s, nowadays, TACE has become a standard treatment for unresectable HCC. 5,6 The anticancer effect of TACE is based on the selective delivery of chemotherapeutic agents into the tumor-feeding arteries, and subsequent ischemic and hypoxic necrosis caused by embolization. According to pre- vious reports, TACE has been proved to significantly improve the survival rate in HCC patients. 5–7 Whereas, accumulating evidence has demonstrated that TACE may lead to the irreversible deterio- ration of liver function as evaluated by the elevation of serum aminotransferases and the decrease of serum albumin (ALB), occasionally resulting in hepatic failure. 8–10 Toxicity of chemo- therapeutics drugs used in TACE has been suggested as the main cause of treat-related complication. 11,12 Owing to selective uptake of the mixture of antineoplastic drugs and iodized oil by tumorous tissue, the side effects of TACE on peritumoral liver tissue are doi:10.1111/jgh.12873 925 Journal of Gastroenterology and Hepatology 30 (2015) 925–932 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd