Decreased expression of zinc-alpha2-glycoprotein in hepatocellular carcinoma associates with poor prognosis

Journal of Translational Medicine

Jing-Ping Yun¹  Yan Li¹  Mu-Yan Cai¹  Guo-Bing Xie¹  Xuan Zhou¹  Li-Li Liu¹  Chun Yi¹  Chris Zhi-Yi Zhang¹  Lin-Zi Li¹  Yan Huang¹ 

[1] Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China, Sun Yat-Sen University Cancer Center, No 651, East Dongfeng Road, Guangzhou, 510060, China

关键词: Metastasis;    Recurrence;    Prognosis;    Hepatocellular carcinoma;    AZGP1;   

Others  :  1205975
DOI  :  10.1186/1479-5876-10-106

 received in 2012-03-15, accepted in 2012-05-09,  发布年份 2012

【 摘 要 】

Background

Zinc-alpha2-glycoprotein (AZGP1, ZAG) was recently demonstrated to be an important factor in tumor carcinogenesis. However, AZGP1 expression in hepatocellular carcinoma (HCC) and its significance remain largely unknown.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to determine mRNA level of AZGP1 in 20 paired fresh HCC tissues. Clinical and pathological data of 246 HCC patients were collected. Tissue-microarray-based immunohistochemistry (IHC) was performed to examine AZGP1 expression in HCC samples. Relationship between AZGP1 expression and clinicopathological features was analyzed by Chi-square test, Kaplan-Meier analysis and Cox proportional hazards regression model.

Results

AZGP1 expression was significantly lower in 80.0% (16/20) of tumorous tissues than that in the corresponding adjacent nontumorous liver tissues (P < 0.001). Consistently, IHC data revealed that decreased expression of AZGP1 was present in 80.1% (197/246) of HCC patient tissues (P < 0.001). Furthermore, AZGP1 expression in HCC significantly associated with several clinicopathological parameters, including serum AFP level (P = 0.013), liver cirrhosis (P = 0.002) and tumor differentiation (P = 0.025). Moreover, HCC patients with high AZGP1 expression survived longer, with better overall survival (P = 0.006) and disease-free survival (P = 0.025). In addition, low AZGP1 expression associated with worse relapse-free survival (P = 0.046) and distant metastatic progression-free survival (P = 0.036).

Conclusion

AZGP1 was downregulated in HCC and could be served as a promising prognostic marker for HCC patients.

【 授权许可】

   
2012 Huang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Lau WY, Lai EC, Lau SH: The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma: a systematic review. Hepatobiliary Pancreat Dis Int 2009, 8:124-133.
• [2]Zheng L, Liang P, Li J, Huang XB, Wang WW, Wang L, Feng H: Expression of BC047440 protein in hepatocellular carcinoma and its relationship to prognosis. Chin J Cancer 2010, 29:931-936.
• [3]Aravalli RN, Steer CJ, Cressman EN: Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008, 48:2047-2063.
• [4]Marra M, Sordelli IM, Lombardi A, Lamberti M, Tarantino L, Giudice A, Stiuso P, Abbruzzese A, Sperlongano R, Accardo M, et al.: Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med 2011, 9:171. BioMed Central Full Text
• [5]Caraglia M, Giuberti G, Marra M, Addeo R, Montella L, Murolo M, Sperlongano P, Vincenzi B, Naviglio S, Prete SD, et al.: Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR. Cell Death Dis 2011, 2:e150.
• [6]Frau M, Biasi F, Feo F, Pascale RM: Prognostic markers and putative therapeutic targets for hepatocellular carcinoma. Mol Aspects Med 2010, 31:179-193.
• [7]Colombino M, Sperlongano P, Izzo F, Tatangelo F, Botti G, Lombardi A, Accardo M, Tarantino L, Sordelli I, Agresti M, et al.: BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy. Cell Death Dis 2012, 3:e259.
• [8]Hassan MI, Waheed A, Yadav S, Singh TP, Ahmad F: Zinc alpha 2-glycoprotein: a multidisciplinary protein. Mol Cancer Res 2008, 6:892-906.
• [9]Zorin NA, Zorina VN, Zorina RM: Role of proteins of the macroglobulin family in regulation of tumor growth. Ontogenez 2006, 37:12-19.
• [10]Zorin NA, Zorina VN, Zorina RM: The role of macroglobulin family proteins in the regulation of inflammation. Biomed Khim 2006, 52:229-238.
• [11]Tada T, Ohkubo I, Niwa M, Sasaki M, Tateyama H, Eimoto T: Immunohistochemical localization of Zn-alpha 2-glycoprotein in normal human tissues. J Histochem Cytochem 1991, 39:1221-1226.
• [12]He N, Brysk H, Tyring SK, Ohkubo I, Brysk MM: Zinc-alpha(2)-glycoprotein hinders cell proliferation and reduces cdc2 expression. J Cell Biochem Suppl 2001, 36(Suppl):162-169.
• [13]Kong B, Michalski CW, Hong X, Valkovskaya N, Rieder S, Abiatari I, Streit S, Erkan M, Esposito I, Friess H, Kleeff J: AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-beta-mediated ERK signaling. Oncogene 2010, 29:5146-5158.
• [14]Albertus DL, Seder CW, Chen G, Wang X, Hartojo W, Lin L, Silvers A, Thomas DG, Giordano TJ, Chang AC, et al.: AZGP1 autoantibody predicts survival and histone deacetylase inhibitors increase expression in lung adenocarcinoma. J Thorac Oncol 2008, 3:1236-1244.
• [15]Diez-Itza I, Sanchez LM, Allende MT, Vizoso F, Ruibal A, Lopez-Otin C: Zn-alpha 2-glycoprotein levels in breast cancer cytosols and correlation with clinical, histological and biochemical parameters. Eur J Cancer 1993, 29A:1256-1260.
• [16]Hale LP, Price DT, Sanchez LM, Demark-Wahnefried W, Madden JF: Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer. Clin Cancer Res 2001, 7:846-853.
• [17]Brysk MM, Lei G, Adler-Storthz K, Chen Z, Brysk H, Tyring SK, Arany I: Zinc-alpha2-glycoprotein expression as a marker of differentiation in human oral tumors. Cancer Lett 1999, 137:117-120.
• [18]Henshall SM, Horvath LG, Quinn DI, Eggleton SA, Grygiel JJ, Stricker PD, Biankin AV, Kench JG, Sutherland RL: Zinc-alpha2-glycoprotein expression as a predictor of metastatic prostate cancer following radical prostatectomy. J Natl Cancer Inst 2006, 98:1420-1424.
• [19]Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M, Egevad L, Rayford W, Bergerheim U, et al.: Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A 2004, 101:811-816.
• [20]Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007, 25:2586-2593.
• [21]Sobin LH, Fleming ID: TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997, 80:1803-1804.
• [22]Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998, 4:844-847.
• [23]Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT: COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 2000, 89:2637-2645.
• [24]Li M, Luo RZ, Chen JW, Cao Y, Lu JB, He JH, Wu QL, Cai MY: High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma. J Transl Med 2011, 9:5. BioMed Central Full Text
• [25]Irmak S, Tilki D, Heukeshoven J, Oliveira-Ferrer L, Friedrich M, Huland H, Ergun S: Stage-dependent increase of orosomucoid and zinc-alpha2-glycoprotein in urinary bladder cancer. Proteomics 2005, 5:4296-4304.
• [26]Abdul-Rahman PS, Lim BK, Hashim OH: Expression of high-abundance proteins in sera of patients with endometrial and cervical cancers: analysis using 2-DE with silver staining and lectin detection methods. Electrophoresis 2007, 28:1989-1996.
• [27]Lei G, Arany I, Selvanayagam P, Rajaraman S, Ram S, Brysk H, Tyring SK, Brysk MM: Detection and cloning of epidermal zinc-alpha 2-glycoprotein cDNA and expression in normal human skin and in tumors. J Cell Biochem 1997, 67:216-222.
• [28]Mazoujian G: Apocrine carcinoma of the breast. Am J Clin Pathol 1990, 94:485-486.
• [29]Descazeaud A, de la Taille A, Allory Y, Faucon H, Salomon L, Bismar T, Kim R, Hofer MD, Chopin D, Abbou CC, Rubin MA: Characterization of ZAG protein expression in prostate cancer using a semi-automated microscope system. Prostate 2006, 66:1037-1043.
• [30]Gagnon S, Tetu B, Dube JY, Tremblay RR: Expression of Zn-alpha 2-glycoprotein and PSP-94 in prostatic adenocarcinoma. An immunohistochemical study of 88 cases. Am J Pathol 1990, 136:1147-1152.
• [31]Dubois V, Delort L, Mishellany F, Jarde T, Billard H, Lequeux C, Damour O, Penault-Llorca F, Vasson MP, Caldefie-Chezet F: Zinc-alpha2-glycoprotein: a new biomarker of breast cancer? Anticancer Res 2010, 30:2919-2925.
• [32]Bing C, Bao Y, Jenkins J, Sanders P, Manieri M, Cinti S, Tisdale MJ, Trayhurn P: Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc Natl Acad Sci U S A 2004, 101:2500-2505.
• [33]Russell ST, Tisdale MJ: Effect of eicosapentaenoic acid (EPA) on expression of a lipid mobilizing factor in adipose tissue in cancer cachexia. Prostaglandins Leukot Essent Fatty Acids 2005, 72:409-414.
• [34]Lapointe J, Malhotra S, Higgins JP, Bair E, Thompson M, Salari K, Giacomini CP, Ferrari M, Montgomery K, Tibshirani R, et al.: hCAP-D3 expression marks a prostate cancer subtype with favorable clinical behavior and androgen signaling signature. Am J Surg Pathol 2008, 32:205-209.