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ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma

Oncogene volume 33, pages 1395–1406 (2014)Cite this article

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Abstract

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.

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Acknowledgements

This study was supported by combined grants from the National Natural Science Foundation of China (No. 81272652, No. 81172290, No. 91129723, No.81090270, No.81090273 and No.81120108005), the National Key and Basic Research Development Program of China (No. 2010CB529302 and 2010CB529306), the National Municipal Science and Technology Project (2009ZX09103-667 and 2009ZX09301-009-RC06) and the Chinese Postdoctoral Science Foundation (No. 20100471776 and No.201104757).

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  1. L Xia and W Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

    L Xia, W Huang, Z Chen, L Zhang, H Hu, J Liu, Z Chen, G Tang, J Dou, S Sha, B Xu, C Liu, J Ma, S Zhang, M Li, D Fan, Y Nie & K Wu

  2. Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China

    D Tian

  3. University of British Columbia, Vancouver, British Columbia, Canada

    Y Li

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  1. L Xia
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Correspondence to Y Nie or K Wu.

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Xia, L., Huang, W., Tian, D. et al. ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Oncogene 33, 1395–1406 (2014). https://doi.org/10.1038/onc.2013.90

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