ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma
ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma
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ACP5是FoxM1的直接转录靶标，可促进肿瘤转移并预示肝细胞癌的不良预后
作者：
Xia, L.;Huang, W.;Wu, K.
抗酒石酸酸性磷酸酶5（ACP 5）是骨吸收和破骨细胞分化所必需的，通过调节粘着斑激酶磷酸化促进细胞运动。然而，ACP 5是否有助于肝细胞癌（HCC）的转移和进展仍不清楚。本论文通过互补基因芯片、序列缺失、定点突变和染色质免疫沉淀等实验证实了ACP 5是Forkhead box M1（FoxM 1）的直接转录靶点。ACP 5在肝癌组织中的表达明显高于癌旁组织。ACP 5过表达与微血管浸润、低分化、高淋巴结转移有关。ACP 5阳性表达的HCC患者预后差于ACP 5阴性表达的HCC患者。多变量分析显示，ACP 5表达是根治性切除术后疾病复发和患者生存率降低的独立且重要的危险因素。Transwell实验和原位转移模型显示，ACP 5的上调促进了HCC侵袭和肺转移，而ACP 5的敲低抑制了这些过程。ACP 5的敲低显著减弱了FoxM 1增强的侵袭和肺转移。免疫组化结果显示，ACP 5和FoxM 1在人肝癌组织中的表达呈正相关，二者的共同表达与肝癌的预后不良有关。总之，ACP 5是FoxM 1的直接转录和功能靶点。这种新的FoxM 1/ACP 5信号通路促进HCC转移，可能是预后的候选生物标志物和新疗法的靶点。
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.