Deregulated AJAP1/\u03b2-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis

Jianyong Han ,Guangchao Yang,Yifeng Cui,Tongsen Zhen,Yan Wang,Tiemin Pei,Xuehui Hong,Yuejin Li,Huawen Shi,Xirui Liu,Jiabei Wang,Keyu Li,Shangha Pan,Kaimin Huang ,Ran Song ,Bei Sun ,Fei Liao,Yaliang Lan,Mingxi Zhu,F Meng ,Xianmin Meng ,Jiewu Zhang,Changming Xie,Fengyue Wang,Yao Liu,Yingjian Liang,Lianxin Liu

doi:10.1038/cddis.2017.126

Abstract

Adherens junctions-associated protein 1 (AJAP1) is an integral membrane protein that is thought to function as a tumor suppressor in various malignancies. Downregulation of AJAP1 mRNA levels may predict recurrence in hepatocellular carcinoma (HCC) patients, but the underlying molecular mechanism is unknown. This was addressed in the present study by examining the role of AJAP1 in HCC cell proliferation, migration, and invasion in vitro as well as in human specimens and mouse xenograft model. We found that AJAP1 expression was reduced in HCC cells and human HCC tissue, which was associated with metastasis. AJAP1 overexpression inhibited HCC progression and metastasis, while its silencing had the opposite effect both in vitro and in vivo. Furthermore, AJAP1 blocked epithelial–to–mesenchymal transition by interacting with β-catenin and inhibiting its nuclear translocation, which suppressed zinc finger E-box binding homeobox 1 (ZEB1) transcription. These results indicate that AJAP1 inhibits HCC metastasis, and is thus a potential therapeutic target for HCC treatment.

Highlights

Hepatocellular carcinoma (HCC) accounts for 85–90% of cases of primary liver cancer, which is the fifth most common malignancy and the third leading cause of cancer mortality.[1]
AJAP1 is downregulated in human HCC, which is negatively correlated with HCC metastasis
Cell Death and Disease western blotting and real-time PCR (Figure 1d). These results indicate that AJAP1 expression is negatively correlated with HCC metastasis and poor prognosis in patients

Summary

Introduction

Hepatocellular carcinoma (HCC) accounts for 85–90% of cases of primary liver cancer, which is the fifth most common malignancy and the third leading cause of cancer mortality.[1]. Surgical resection is the most common treatment for HCC; the frequency of tumor recurrence and distant metastasis remains high. The precise role of AJAP1 in HCC progression remains unknown. This was addressed in the present study using HCC patient tissue specimens, HCC cells, and mouse xenograft model. We found that AJAP1 has a tumor-suppressor role in HCC and inhibits HCC cell proliferation and metastasis via β-catenin/zinc finger E-box binding homeobox 1 (ZEB1) signaling

Methods

Results

Conclusion