Abstract
Annexin A1 (ANXA1) belongs to the annexin superfamily of proteins, which contribute to the pathological consequence and sequelae of most serious human diseases. Recent studies have reported diverse roles of ANXA1 in various human cancers; however, its involvement in human hepatocellular carcinoma (HCC) still remains controversial. To investigate the expression pattern of ANXA1 in HCC tissues and evaluate its associations with tumor progression and patients’ prognosis, immunohistochemistry was performed using 160 pairs of formalin-fixed and paraffin-embedded cancerous and adjacent non-cancerous tissues from patients with HCC. Then, the associations between ANXA1 expression, clinicopathological characteristics, and prognosis of HCC patients were statistically evaluated. In vitro migration and invasion assays of siRNA-targeted ANXA1-transfected cells were further performed. As a result, the expression levels of ANXA1 protein in HCC tissues were significantly higher than those in adjacent non-cancerous tissues (P < 0.001). High ANXA1 expression was closely correlated with advanced TNM stage (P = 0.001) and high Edmondson grade (P = 0.02). Then, univariate and multivariate analyses showed that the status of ANXA1 expression was an independent predictor for overall survival of HCC patients. Furthermore, knockdown of ANXA1 by transfection of siRNA–ANXA1 could suppress the migration and invasion abilities of HCC cells in vitro. Collectively, these findings offer the convincing evidence that ANXA1 may play an important role in HCC progression and can be used as a molecular marker to predict prognosis and a potential target for therapeutic intervention of HCC.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.
Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol. 2005;23:2892–9.
Bosch FX, Ribes J, Borràs J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;19:271–85.
El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.
Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev. 2002;82:331–71.
Guo C, Liu S, Sun MZ. Potential role of Anxa1 in cancer. Future Oncol. 2013;9:1773–93.
Bist P, Shu S, Lee H, Arora S, Nair S, Lim JY, Dayalan J, Gasser S, Biswas SK, Fairhurst AM, Lim LH. Annexin-A1 regulates TLR-mediated IFN-β production through an interaction with TANK-binding kinase 1. J Immunol. 2013;191:4375–82.
Boudhraa Z, Rondepierre F, Ouchchane L, Kintossou R, Trzeciakiewicz A, Franck F, Kanitakis J, Labeille B, Joubert-Zakeyh J, Bouchon B, Perrot JL, Mansard S, Papon J, Dechelotte P, Chezal JM, Miot-Noirault E, Bonnet M, D’Incan M, Degoul F. Annexin A1 in primary tumors promotes melanoma dissemination. Clin Exp Metastasis. 2014;31:749–60.
Kang H, Ko J, Jang SW. The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells. Biochem Biophys Res Commun. 2012;423:188–94.
Gao Y, Chen Y, Xu D, Wang J, Yu G. Differential expression of ANXA1 in benign human gastrointestinal tissues and cancers. BMC Cancer. 2014;14:520.
Su N, Xu XY, Chen H, Gao WC, Ruan CP, Wang Q, Sun YP. Increased expression of annexin A1 is correlated with K-ras mutation in colorectal cancer. Tohoku J Exp Med. 2010;222:243–50.
Sheu MJ, Li CF, Lin CY, Lee SW, Lin LC, Chen TJ, Ma LJ. Overexpression of ANXA1 confers independent negative prognostic impact in rectal cancers receiving concurrent chemoradiotherapy. Tumour Biol. 2014;35:7755–63.
Rossi AF, Duarte MC, Poltronieri AB, Valsechi MC, Jorge YC, de-Santi Neto D, Rahal P, Oliani SM, Silva AE. Deregulation of annexin-A1 and galectin-1 expression in precancerous gastric lesions: intestinal metaplasia and gastric ulcer. Mediators Inflamm. 2014;2014:478138.
Zhang ZQ, Li XJ, Liu GT, Xia Y, Zhang XY, Wen H. Identification of annexin A1 protein expression in human gastric adenocarcinoma using proteomics and tissue microarray. World J Gastroenterol. 2013;19:7795–803.
Han G, Tian Y, Duan B, Sheng H, Gao H, Huang J. Association of nuclear annexin A1 with prognosis of patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7:751–9.
Jorge YC, Mataruco MM, Araújo LP, Rossi AF, de Oliveira JG, Valsechi MC, Caetano A, Miyazaki K, Fazzio CS, Thomé JA, Rahal P, Oliani SM, Silva AE. Expression of annexin-A1 and galectin-1 anti-inflammatory proteins and mRNA in chronic gastritis and gastric cancer. Mediators Inflamm. 2013;2013:152860.
Suo A, Zhang M, Yao Y, Zhang L, Huang C, Nan K, Zhang W. Proteome analysis of the effects of sorafenib on human hepatocellular carcinoma cell line HepG2. Med Oncol. 2012;29:1827–36.
Hongsrichan N, Rucksaken R, Chamgramol Y, Pinlaor P, Techasen A, Yongvanit P, Khuntikeo N, Pairojkul C, Pinlaor S. Annexin A1: a new immunohistological marker of cholangiocarcinoma. World J Gastroenterol. 2013;19:2456–65.
Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.
Jiang SS, Weng DS, Wang QJ, Pan K, Zhang YJ, Li YQ, Li JJ, Zhao JJ, He J, Lv L, Pan QZ, Xia JC. Galectin-3 is associated with a poor prognosis in primary hepatocellular carcinoma. J Transl Med. 2014;12:273.
Cao Z, Fu B, Deng B, Zeng Y, Wan X, Qu L. Overexpression of Chemokine (C-X-C) ligand 1 (CXCL1) associated with tumor progression and poor prognosis in hepatocellular carcinoma. Cancer Cell Int. 2014;14:86.
Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8:138–40.
El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.
Ang EZ, Nguyen HT, Sim HL, Putti TC, Lim LH. Annexin-1 regulates growth arrest induced by high levels of estrogen in MCF-7 breast cancer cells. Mol Cancer Res. 2009;7:266–74.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lin, Y., Lin, G., Fang, W. et al. Increased expression of annexin A1 predicts poor prognosis in human hepatocellular carcinoma and enhances cell malignant phenotype. Med Oncol 31, 327 (2014). https://doi.org/10.1007/s12032-014-0327-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-014-0327-7