State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China.
Oncogene. 2014 Mar 13;33(11):1395-406. doi: 10.1038/onc.2013.90. Epub 2013 Apr 22.
Tartrate-resistant acid phosphatase 5 (ACP5), which is essential for bone resorption and osteoclast differentiation, promotes cell motility through the modulation of focal adhesion kinase phosphorylation. However, whether ACP5 contributes to the metastasis and progression of hepatocellular carcinoma (HCC) remains unknown. In this paper, a complementary DNA microarray, serial deletion, site-directed mutagenesis and a chromatin immunoprecipitation assays confirmed that ACP5 is a direct transcriptional target of Forkhead box M1 (FoxM1). ACP5 expression was markedly higher in HCC tissues compared with adjacent noncancerous tissues. ACP5 overexpression was correlated with microvascular invasion, poor differentiation and higher tumor-node-metastasis stage. HCC patients with positive ACP5 expression had poorer prognoses than those with negative ACP5 expression. A multivariate analysis revealed that ACP5 expression was an independent and significant risk factor for disease recurrence and reduced-patient survival following curative resection. Transwell assays and an orthotopic metastatic model showed that the upregulation of ACP5 promoted HCC invasion and lung metastasis, whereas ACP5 knockdown inhibited these processes. The knockdown of ACP5 significantly attenuated FoxM1-enhanced invasion and lung metastasis. Immunohistochemistry revealed that ACP5 expression was positively correlated with FoxM1 expression in human HCC tissues, and their coexpression was associated with poor prognoses. In summary, ACP5 is a direct transcriptional and functional target of FoxM1. This novel FoxM1/ACP5 signaling pathway promotes HCC metastasis and may be a candidate biomarker for prognosis and a target for new therapies.
耐酒石酸酸性磷酸酶 5（ACP5）对于骨吸收和破骨细胞分化至关重要，通过调节粘着斑激酶磷酸化促进细胞迁移。然而，ACP5 是否促进肝细胞癌（HCC）的转移和进展尚不清楚。在本文中，通过 cDNA 微阵列、串联缺失、定点诱变和染色质免疫沉淀实验证实 ACP5 是叉头框蛋白 M1（FoxM1）的直接转录靶标。与相邻非癌组织相比，HCC 组织中 ACP5 的表达明显更高。ACP5 的过表达与微血管侵犯、分化不良和更高的肿瘤-淋巴结-转移分期相关。ACP5 表达阳性的 HCC 患者预后较 ACP5 表达阴性的患者差。多变量分析显示，ACP5 表达是疾病复发和根治性切除后患者生存时间缩短的独立且显著的危险因素。Transwell 分析和原位转移模型表明，ACP5 的上调促进了 HCC 的侵袭和肺转移，而 ACP5 的敲低则抑制了这些过程。ACP5 的敲低显著减弱了 FoxM1 增强的侵袭和肺转移。免疫组化显示 ACP5 在人 HCC 组织中的表达与 FoxM1 的表达呈正相关，并且它们的共表达与预后不良相关。综上所述，ACP5 是 FoxM1 的直接转录和功能靶标。该新的 FoxM1/ACP5 信号通路促进 HCC 转移，可能成为预后的候选生物标志物和新治疗靶点。
