Wang Guodong, Liu Jian, Cai Yi, Chen Jie, Xie Wenbing, Kong Xiangqian, Huang Wenjie, Guo Hao, Zhao Xiaodi, Lu Yuanyuan, Niu Lu, Li Xiaowei, Zhang Haijia, Lei Chao, Lei Zhijie, Yin Jipeng, Hu Hao, Yu Fan, Nie Yongzhan, Xia Limin, Wu Kaichun
State 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.
Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Oncotarget. 2017 May 30;8(42):71867-71880. doi: 10.18632/oncotarget.18288. eCollection 2017 Sep 22.
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 and matrix metallopeptidase 9 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.
转移是肝细胞癌（HCC）手术治疗后预后不良的主要原因。然而，转移的分子机制尚未得到充分阐明。在此，我们报道了Barx同源盒1（Barx1）在抑制HCC侵袭和转移方面的新功能。与相邻非肿瘤组织和正常肝组织相比，Barx1在人类HCC组织中的表达显著降低。Barx1低表达与更高的肿瘤-结节-转移分期相关，并提示预后不良。Barx1的下调促进HCC的迁移、侵袭和转移，而Barx1的上调则抑制HCC的迁移、侵袭和转移。甘露糖基（α-1,6-）-糖蛋白β-1,6-N-乙酰葡糖胺基转移酶5和基质金属蛋白酶9是Barx1的直接靶基因。在低转移能力的HCC细胞中，敲低Barx1会上调MGAT5和MMP9的表达，而在高转移能力的HCC细胞中，过表达Barx1会抑制它们的表达。同时敲低MGAT5和MMP9可显著降低由Barx1敲低诱导的侵袭和转移能力。在人类HCC组织中，Barx1表达与MGAT5和MMP9表达呈负相关。Barx1低表达且MGAT5或MMP9高表达的患者预后较差。因此，Barx1的缺失是人类HCC患者的一种预后生物标志物。
