Loss of Barx1 promotes hepatocellular carcinoma metastasis through up-regulating MGAT5 and MMP9 expression and indicates poor prognosis
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Guodong Wang1,*, Jian Liu1,*, Yi Cai2,*, Jie Chen3,*, Wenbing Xie2, Xiangqian Kong2, Wenjie Huang1,4, Hao Guo1, Xiaodi Zhao1, Yuanyuan Lu1, Lu Niu1, Xiaowei Li1, Haijia Zhang1, Chao Lei1, Zhijie Lei1, Jipeng Yin1, Hao Hu5, Fan Yu6, Yongzhan Nie1, Limin Xia1,4 and Kaichun Wu1
1State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, People’s Republic of China
2Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
3Department of Orthopedic Oncology, Tangdu Hospital of Fourth Military Medical University, Xi’an 710038, Shaanxi Province, People’s Republic of China
4Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, People’s Republic of China
5Department of Gastroenterology, the Fifth Hospital of the People’s Liberation Army, Yinchuan 750000, Ningxia Province, People’s Republic of China
6State Key Laboratory of Military Stomatology & National Clinical Research Centre for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi’an 710032, People’s Republic of China
*These authors have contributed equally to this work
Limin Xia, email: [email protected]
Kaichun Wu, email: [email protected]
Keywords: hepatocellular carcinoma, barx homeobox 1, mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase 5, matrix metallopeptidase 9, metastasis
Received: February 28, 2017 Accepted: May 07, 2017 Published: May 30, 2017
Metastasis is the major dominant reason for poor prognosis of hepatocellular carcinoma (HCC) after surgical treatment. However, the molecular mechanism of metastasis has not been well characterzied. Here, we report a novel function of Barx homeobox1 (Barx1) in inhibiting HCC invasion and metastasis. Barx1 expression is significantly decreased in human HCC tissues than in adjacent non-tumorous tissues and normal liver tissues. Low Barx1 expression is correlated with higher tumor-nodule-metastasis stage and indicates poor prognosis. Down-regulation of Barx1 promotes HCC migration, invasion and metastasis, whereas up-regulation of Barx1 inhibits HCC migration, invasion and metastasis. Mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase 5 (MGAT5) and matrix metallopeptidase 9 (MMP9) are direct target genes of Barx1. Knockdown of Barx1 up-regulates MGAT5 and MMP9 expression in HCC cells with low metastatic capability, whereas over-expression of Barx1 suppresses their expression in HCC cells with high metastatic capability. Knockdown of both MGAT5 and MMP9 significantly decreases the invasion and metastasis abilities induced by Barx1 knockdown. Barx1 expression is negatively correlated with MGAT5 and MMP9 expression in human HCC tissues. Patients with low expression of Barx1 and high expression of MGAT5 or MMP9 are associated with poorer prognosis. Thus, loss of Barx1 represents a prognostic biomarker in human HCC patients.
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