Abstract 2693: ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma.
Authors: Limin Xia, Daiming Fan, Yongzhan Nie, Kaichun Wu
Journal: Cancer Research (2013)

Abstract Background and aims: Metastasis is the major reason for the high mortality of HCC patients after curative resection. Nonetheless, the molecular mechanisms underlying HCC metastasis remain largely unclear. Forkhead box M1 (FoxM1) is a master regulator of tumor metastasis. We previously reported that FoxM1 promoted metastasis and indicated poor prognosis in HCC. Using a cDNA microarray, we found that FoxM1 upregulated a number of metastatic-related genes expression. Of particular interest was Tartrate-resistant acid phosphatase 5 (ACP5). ACP5 has been shown to be significantly upregulated in breast cancer and melanoma and is a useful serum marker for extensive bone metastasis. We hypothesize that FoxM1-mediated ACP5 expression may play a role in HCC metastasis. Therefore, the aim of this study was to investigate the clinicopathologic significance of ACP5 in HCC and the potential role of ACP5 in FoxM1-mediated invasiveness and metastasis. Methods: This study employed a tissue microarray containing samples from 406 HCC patients who underwent curative resection to examine the expression of ACP5 and its correlation with clinicopathological characteristics. The effect of ACP5 on FoxM1-mediated invasiveness and metastasis were performed by transwell assays and an orthotopically metastatic model. Results: Serial deletion, site-directed mutagenesis, and a chromatin immunoprecipitation assays confirmed that ACP5 is a direct transcriptional target of 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 prognosis 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. ACP5 promotes cell motility through the inhibition of focal adhesion kinase (FAK) phosphorylation at Tyr397. 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. Patients with positive coexpression of FoxM1 and ACP5 had shorter overall survival and higher recurrence times than those with negative coexpresssion of FoxM1 and ACP5. Conclusions: 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. Citation Format: Limin Xia, Daiming Fan, Yongzhan Nie, Kaichun Wu. ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2013-2693 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.