Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma

Li Ming Zhu,Wei Yan Yao,Min Min Qiao,Yan Fei Ding,Qiang Dai,Yun Lin Wu,Xiao Jiao Cheng,Shui Ping Tu,Shi Hu Jiang,Ping Hu Sun,Dong Mei Shi

doi:10.18632/oncotarget.2114

Li Ming Zhu, Wei Yan Yao + Show 9 more

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https://doi.org/10.18632/oncotarget.2114

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Abstract

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment.

Highlights

Hepatocellular carcinoma (HCC) is involved in multiple gene alterations including tumor suppressor inactivation, oncogene activation and apoptosis-related gene dysregulation [1]
Western blot showed that XIAP-associated factor 1 (XAF1) expression was lower in liver cancer tissues than that in the paired non-HCC tissues (Fig. 1B)
The results showed that the apoptotic rate were significantly higher in all 3 HCC cell lines treated with the combination of Ad5/ F35-XAF1 and 5- Fluorouracil (5-FU) than those in the cell treated with Ad5/F35-XAF1 and 5-FU alone (Fig. 3D), suggesting that Ad5/F35-XAF1 cooperates with 5-FU to induce apoptosis of HCC cells

Summary

Introduction

Hepatocellular carcinoma (HCC) is involved in multiple gene alterations including tumor suppressor inactivation, oncogene activation and apoptosis-related gene dysregulation [1]. Many studies have shown that inhibition of apoptosis plays an important role in tumor growth and drug resistance [2]. IAPs are characterized by highly conserved Baculoviral IAP Repeats (BIR) that inhibit apoptosis and include 8 members [5]. X-linked IAP (XIAP) is the most potent member of human IAPs that inhibit the role of caspases [6]. XIAP has been shown to be overexpressed in most human cancer cell lines and cancer tissues including HCC tissues. Studies have shown that XIAP antisense nucleic acid and small molecule inhibitors of XIAP induce apoptosis and inhibit tumor growth in HCC cells [9], indicating that targeting inhibition of XIAP may be a new approach for HCC therapy [10]

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