Combined aberrant expression of N-Myc downstream-regulated gene 2 and CD24 is associated with disease-free survival and overall survival in patients with hepatocellular carcinoma

Diagnostic Pathology

Guofeng Chen¹  Xiaodong Guo¹  Fan Li¹  Dong Ji¹  Qing Shao¹  Bing Li¹ 

[1] Liver Fibrosis Diagnosis and Treatment Center, Beijing 302 Hospital, Beijing 100039, China

关键词: Overall survival;    Disease-free survival;    Hepatocellular carcinoma;    CD24;    N-Myc downstream-regulated gene 2;   

Others  :  1149431
DOI  :  10.1186/s13000-014-0209-5

 received in 2014-08-26, accepted in 2014-10-08,  发布年份 2014

【 摘 要 】

Background

N-Myc downstream-regulated gene 2 (NDRG2), as a tumor suppressor, has been demonstrated to inhibit tumor invasion and migration of hepatocellular carcinoma (HCC) by reducing the expression of CD24, which has been identified as a prognostic factor for HCC patients. However, the clinical significance of combined NDRG2 and CD24 expression in HCC remains unclear. Thus, the aim of the current study was to investigate the relationship of NDRG2 and CD24 expression with clinicopathological parameters and patients¿ survival.

Methods

Immunohistochemistry was performed to detect the expression and subcellular localizations of NDRG2 and CD24 proteins in 130 pairs of HCC and adjacent nonneoplastic liver tissues.

Results

NDRG2 protein was strongly expressed in the cytoplasm and plasma membrane of hepatocytes in adjacent nonneoplastic liver tissues, whereas its immunostaining was weak or negative in HCC tissues. In contrast, CD24 protein exhibited the cytoplasm immunostaining in tumor cells of HCC tissues but showed negative expression in adjacent nonneoplastic liver tissues. The statistical analysis also showed that the expression levels of NDRG2 and CD24 proteins in HCC tissues were respectively lower and higher than those in adjacent nonneoplastic liver tissues significantly (both P?

Conclusions

These findings suggest that the downregulation of NDRG2 combined with the upregulation of CD24 may play a synergistic role in the occurrence and progression of HCC. A combined detection of NDRG2/CD24 expression may benefit us in determining the prognosis in patients with HCC.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_209 webcite

【 授权许可】

   
2014 Li et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Kiyosawa K, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K, Gad A, Tanaka E: Hepatocellular carcinoma: recent trends in Japan. Gastroenterology 2004, 127:S17-S26.
• [3]Nguyen VT, Law MG, Dore GJ: Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat 2009, 16:453-463.
• [4]Dhanasekaran R, Limaye A, Cabrera R: Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepat Med 2012, 4:19-37.
• [5]Mordalska A, Latek J, Ferenc T, Pomorski L, Ga?ecka E, Zygmunt A, Lewi?ski A: Evaluation of NDRG2 gene expression in primary papillary thyroid carcinoma and in metastases of this neoplasm to regional lymph nodes. Thyroid Res 2010, 3:6. BioMed Central Full Text
• [6]Kim MJ, Lim J, Yang Y, Lee MS, Lim JS: N-myc downstream-regulated gene 2 (NDRG2) suppresses the epithelial-mesenchymal transition (EMT) in breast cancer cells via STAT3/Snail signaling. Cancer Lett 2014, 354:33-42.
• [7]Liu J, Zhang J, Wang X, Li Y, Chen Y, Li K, Zhang J, Yao L, Guo G: HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res 2010, 316:1985-1993.
• [8]Deng Y, Yao L, Chau L, Ng SS, Peng Y, Liu X, Au WS, Wang J, Li F, Ji S, Han H, Nie X, Li Q, Kung HF, Leung SY, Lin MC: N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int J Cancer 2003, 106:342-347.
• [9]Zhao H, Zhang J, Lu J, He X, Chen C, Li X, Gong L, Bao G, Fu Q, Chen S, Lin W, Shi H, Ma J, Liu X, Ma Q, Yao L: Reduced expression of N-Myc downstream-regulated gene 2 in human thyroid cancer. BMC Cancer 2008, 8:303. BioMed Central Full Text
• [10]Liang ZL, Kang K, Yoon S, Huang SM, Lim JS, Kim JM, Lim JS, Lee HJ: NDRG2 is involved in the oncogenic properties of renal cell carcinoma and its loss is a novel independent poor prognostic factor after nephrectomy. Ann Surg Oncol 2012, 19:2763-2772.
• [11]Lorentzen A, Lewinsky RH, Bornholdt J, Vogel LK, Mitchelmore C: Expression profile of the N-myc Downstream Regulated Gene 2 (NDRG2) in human cancers with focus on breast cancer. BMC Cancer 2011, 11:14. BioMed Central Full Text
• [12]Lee DC, Kang YK, Kim WH, Jang YJ, Kim DJ, Park IY, Sohn BH, Sohn HA, Lee HG, Lim JS, Kim JW, Song EY, Kim DM, Lee MN, Oh GT, Kim SJ, Park KC, Yoo HS, Choi JY, Yeom YI: Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis. Cancer Res 2008, 68:4210-4220.
• [13]Feng L, Xie Y, Zhang H, Wu Y: Down-regulation of NDRG2 gene expression in human colorectal cancer involves promoter methylation and microRNA-650. Biochem Biophys Res Commun 2011, 406:534-538.
• [14]Yu C, Wu G, Dang N, Zhang W, Zhang R, Yan W, Zhao Y, Gao L, Wang Y, Beckwith N, Yuan J, Yao L: Inhibition of N-myc downstream-regulated gene 2 in prostatic carcinoma. Cancer Biol Ther 2011, 12:304-313.
• [15]Yao L, Zhang J, Liu X: NDRG2: a Myc-repressed gene involved in cancer and cell stress. Acta Biochim Biophys Sin (Shanghai) 2008, 40:625-635.
• [16]Liu N, Wang L, Liu X, Yang Q, Zhang J, Zhang W, Wu Y, Shen L, Zhang Y, Yang A, Han H, Zhang J, Yao L: Promoter methylation, mutation, and genomic deletion are involved in the decreased NDRG2 expression levels in several cancer cell lines. Biochem Biophys Res Commun 2007, 358:164-169.
• [17]Choi SC, Yoon SR, Park YP, Song EY, Kim JW, Kim WH, Yang Y, Lim JS, Lee HG: Expression of NDRG2 is related to tumor progression and survival of gastric cancer patients through Fas-mediated cell death. Exp Mol Med 2007, 39:705-714.
• [18]Zheng J, Li Y, Yang J, Liu Q, Shi M, Zhang R, Shi H, Ren Q, Ma J, Guo H, Tao Y, Xue Y, Jiang N, Yao L, Liu W: NDRG2 inhibits hepatocellular carcinoma adhesion, migration and invasion by regulating CD24 expression. BMC Cancer 2011, 251:1-9.
• [19]Kristiansen G, Sammar M, Altevogt P: Tumour biological aspects of CD24, a mucin-like adhesion molecule. J Mol Histol 2004, 35:255-262.
• [20]Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Vellon L, Menendez JA: Autophagy positively regulates the CD44(+) CD24(?/low) breast cancer stem-like phenotype. Cell Cycle 2011, 10:3871-3885.
• [21]Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M, Altevogt P: CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 1997, 89:3385-3395.
• [22]Karran L, Jones M, Morley G, Van Noorden S, Smith P, Lampert I, Griffin BE: Expression of a B-cell marker, CD24, on nasopharyngeal carcinoma cells. Int J Cancer 1995, 60:562-566.
• [23]Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R Jr, Badve S, Nakshatri H: CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 2006, 8:R59. BioMed Central Full Text
• [24]Kim HJ, Kim MJ, Ahn SH, Son BH, Kim SB, Ahn JH, Noh WC, Gong G: Different prognostic significance of CD24 and CD44 expression in breast cancer according to hormone receptor status. Breast 2011, 20:78-85.
• [25]Takahashi M, Nakajima M, Ogata H, Domeki Y, Ohtsuka K, Ihara K, Kurayama E, Yamaguchi S, Sasaki K, Miyachi K, Kato H: CD24 expression is associated with progression of gastric cancer. Hepatogastroenterology 2013, 60:653-658.
• [26]Yang XR, Xu Y, Yu B, Zhou J, Li JC, Qiu SJ, Shi YH, Wang XY, Dai Z, Shi GM, Wu B, Wu LM, Yang GH, Zhang BH, Qin WX, Fan J: CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res 2009, 15:5518-5527.
• [27]Thomas S, Harding MA, Smith SC, Overdevest JB, Nitz MD, Frierson HF, Tomlins SA, Kristiansen G, Theodorescu D: CD24 is an effector of HIF-1-driven primary tumor growth and metastasis. Cancer Res 2012, 72:5600-5612.
• [28]Zhu J, Zhang G, Lu H: CD24, COX-2, and p53 in epithelial ovarian cancer and its clinical significance. Front Biosci (Elite Ed) 2012, 4:2745-2751.
• [29]Marmé F, Werft W, Walter A, Keller S, Wang X, Benner A, Burwinkel B, Sinn P, Hug S, Sohn C, Bretz N, Moldenhauer G, Rupp C, Rupp AK, Biakhov MY, Bottini A, Friedrichs K, Khailenko VA, Manikhas GM, Ruiz A, Sánchez-Rovira P, Santoro A, Segui MA, Villena C, Lichter P, Kristiansen G, Altevogt P, Schneeweiss A: CD24 Ala57Val polymorphism predicts pathologic complete response to sequential anthracycline- and taxane-based neoadjuvant chemotherapy for primary breast cancer. Breast Cancer Res Treat. 2011 In press.
• [30]Liu C, Zheng S, Shen H, Xu K, Chen J, Li H, Xu Y, Xu A, Chen B, Kaku H, Nasu Y, Kumon H, Huang P, Watanabe M: Clinical significance of CD24 as a predictor of bladder cancer recurrence. Oncol Lett 2013, 6:96-100.
• [31]Guo X, Xiong L, Zou L, Zhao J: Upregulation of bone morphogenetic protein 4 is associated with poor prognosis in patients with hepatocellular carcinoma. Pathol Oncol Res 2012, 18:635-640.
• [32]Guo X, Xiong L, Sun T, Peng R, Zou L, Zhu H, Zhang J, Li H, Zhao J: Expression features of SOX9 associate with tumor progression and poor prognosis of hepatocellular carcinoma. Diagn Pathol 2012, 7:44. BioMed Central Full Text
• [33]Guo X, Xiong L, Zou L, Sun T, Zhang J, Li H, Peng R, Zhao J: L1 cell adhesion molecule overexpression in hepatocellular carcinoma associates with advanced tumor progression and poor patient survival. Diagn Pathol 2012, 7:96. BioMed Central Full Text
• [34]Gao L, Wu GJ, Liu XW, Zhang R, Yu L, Zhang G, Liu F, Yu CG, Yuan JL, Wang H, Yao LB: Suppression of invasion and metastasis of prostate cancer cells by overexpression of NDRG2 gene. Cancer Lett 2011, 310:94-100.
• [35]Bircan S, Kapucuoglu N, Baspinar S, Inan G, Candir O: CD24 expression in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immunohistochemistry-based pilot study. Pathol Res Pract 2006, 202:569-576.
• [36]Purcell WT, Rudek MA, Hidalgo M: Development of matrix metalloproteinase inhibitors in cancer therapy. Hematol Oncol Clin North Am 2002, 16:1189-1227.
• [37]Bendas G, Borsig L: Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012, 2012:676731.