Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer

Journal of Biomedical Science

Yin-lin Ge²  Li Wu¹  Dong-Liang Lin³  Zhong-liang Ma¹  Ming-Jin Zhou⁴  Lin Hou²  Lin-Lin Han² 

[1] Department of Breast Surgery, the Affiliated Hospital of Qingdao University Medical College, Qingdao, China;Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao 266021, China;Department of Pathology, the Affiliated Hospital of Qingdao University Medical College, Qingdao, China;Department of Clinical Laboratory, Qilu hospital of Shandong University, Jinan, Shandong 250012, China

关键词: N-myc downstream regulated gene;    Gene expression;    DNA methylation;    Breast cancer;   

Others  :  1137636
DOI  :  10.1186/1423-0127-20-52

 received in 2012-10-22, accepted in 2013-07-21,  发布年份 2013

【 摘 要 】

Background

Cancer cell differentiation is an important characteristic of malignant tumor and has a great impact on prognosis and therapeutic decision for patients. The N-myc downstream regulated gene 1 (NDRG1), a putative tumor suppression gene, is involved in the regulation of human cell differentiation and metastasis in various cancers. Changes in the status of methylation of the NDRG1 gene have not been studied in detail in human breast cancer.

Results

The MDA-MB-231 breast tumor cell line could express NDRG1. However, it was only expressed after treatment with 5-Aza-2'-deoxycytidine (AZA) in T47D cell line, which revealed that NDRG1 expression could modulated by DNA methylation. Therefore, the fragment surrounding the transcript start site of NDRG1 gene promoter was cloned after sodium bisulfite DNA treatment. A high density (66%) of methylation for human NDRG1 gene promoter was detected in T47D; however, there was only 16% of methylated CpG dinucleotides in the NDRG1 gene promoter in MDA-MB-231. DNA methylation in the NDRG1 promoter was detected in 31.1% of primary breast cancer samples. Furthermore, the NDRG1 promoter methylation correlated with the Tumor Node Metastasis (TNM) at stage III/IV, metastasis, lymph invasion, moderate and poor histological grade in the breast cancer patients.

Conclusion

These findings suggest that the DNA methylation status of NDRG1 gene may play an important role in the pathogenesis and/or development of breast cancer, and the expression could be regulated by aberrant DNA methylation.

【 授权许可】

   
2013 Han et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]DeSantis C, Siegel R, Bandi P, Jemal A: Breast cancer statistics, 2011. CA Cancer J Clin 2011, 61(6):409-418.
• [2]Van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosman FT: A novel gene which is up-regulated during colon epithelial ell differentiation and down-regulated in colorectal neoplasms. Lab Invest 1997, 77(1):85-92.
• [3]Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D, Commes T, Watabe M, Gross SC, Wang Y, Ran S, Watabe K: Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene 2004, 23(33):5675-5681.
• [4]Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, Metcalf RA, Samet JM, Takeshima Y, Gu JR, et al.: p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 1993, 53(20):4817-4822.
• [5]Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW: Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res 1998, 58(19):4439-4444.
• [6]Clark SJ, Melki J: DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 2002, 21(35):5380-5387.
• [7]Jones PA, Baylin SB: The epigenomics of cancer. Cell 2007, 128(4):683-692.
• [8]Schmutte C, Jones PA: Involvement of DNA methylation in human carcinogenesis. Biol Chem 1998, 379(4–5):377-388.
• [9]Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC: hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 1999, 59(1):159-164.
• [10]Hu S, Cheng L, Wen B: Large chromatin domains in pluripotent and differentiated cells. Acta Biochim Biophys Sin (Shanghai) 2012, 44(1):48-53.
• [11]Fotovati A, Abu-Ali S, Kage M, Shirouzu K, Yamana H, Kuwano M: N-myc downstream-regulated gene 1 (Drg-1) a differentiation marker of human breast cancer. Pathol Oncol Res 2011, 17(3):525-533.
• [12]Angst E, Sibold S, Tiffon C, Weimann R, Gloor B, Candinas D, Stroka D: Cellular differentiation determines the expression of the hypoxia-inducible protein Drg-1 in pancreatic cancer. Br J Cancer 2006, 95(3):307-313.
• [13]Angst E, Dawson DW, Nguyen A, Park J, Go VL, Reber HA, Hines OJ, Eibl G: Epigenetic regulation affects N-myc downstream regulated gene-1 expression indirectly in pancreatic cancer cells. Pancreas 2010, 39(5):675-679.
• [14]Chang X, Zhang S, Ma J, Li Z, Zhi Y, Chen J, Lu Y, Dai D: Association of NDRG1 Gene Promoter Methylation with Reduced NDRG1 Expression in Gastric Cancer Cells and Tissue Specimens. Cell Biochem Biophys 2012, 66(1):93-101.
• [15]Li Q, Chen H: Transcriptional silencing of N-Myc downstream-regulated gene 1 (Drg-1) in metastatic colon cancer cell line SW620. Clin Exp Metastasis 2011, 28(2):127-135.
• [16]Veronesi U, Viale G, Rotmensz N, Goldhirsch A: Rethinking TNM: breast cancer TNM classification for treatment decision-making and research. Breast 2006, 15(1):3-8.
• [17]Zou B, Chim CS, Zeng H, Leung SY, Yang Y, Tu SP, Lin MC, Wang J, He H, Jiang SH, Sun YW, Yu LF, Yuen ST, Kung HF, Wong BC: Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Gastroenterology 2006, 131(6):1835-1843.
• [18]Das PM, Singal R: DNA methylation and cancer. J Clin Oncol 2004, 22(22):4632-4642.
• [19]Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK: N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 2000, 67(1):47-58.
• [20]Schnitt SJ: Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Mod Pathol 2010, 23(Suppl 2):s60-s64.
• [21]Song Y, Oda Y, Hori M, Kuroiwa K, Ono M, Hosoi F, Basaki Y, Tokunaga S, Kuwano M, Naito S, Tsuneyoshi M: N-myc downstream regulated gene-1/ Cap43 may play an important role in malignant progression of prostate cancer, in its close association with E-cadherin. Hum Pathol 2010, 41(2):214-222.
• [22]Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H, Kuwano M: Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res 2006, 66(12):6233-6242.
• [23]Russo J, Mailo D, Hu YF, Balogh G, Sheriff F, Russo IH: Breast differentiation and its implication in cancer prevention. Clin Cancer Res 2005, 11(2 Pt 2):931s-936s.
• [24]Page DL: Prognosis and breast cancer. Recognition of lethal and favorable prognostic types. Am J Surg Pathol 1991, 15(4):334-349.
• [25]Zhang SB, Song SP, Li B, Zhou YS, Zhang YD: Expression of N-myc downstream-regulated gene 1 in primary gallbladder carcinoma and its MDA-MB-231with clinicopathological features and clinical outcome. Med Oncol 2012, 29(3):1866-1872.
• [26]Jiang K, Shen Z, Ye Y, Yang X, Wang S: A novel molecular marker for early detection and evaluating prognosis of gastric cancer: N-myc downstream regulated gene-1 (NDRG1). Scand J Gastroenterol 2010, 45(7–8):898-908.