Aberrant Promoter CpG Islands Methylation of E-cadherin in Human Primary Hepatocellular Carcinomas_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HUANG Wenqing ¹ , YANG Wenli ¹ , CHAI Xinjuan ¹ , CHEN Kefei ² , WEI Ling ¹ , LI Bo ² , QIN Yang ¹

1.Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center, Sichuan University, Chengdu 610041, Sichuan Province, China;;
2.Department of Hepatic Surgery and Vascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China;

Corresponding author：

Keywords：

Hepatocellular carcinoma; E-cadherin gene; CpG island; DNA methylation

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ObjectiveTo explore the relationship between aberrant promoter CpG islands methylation status of E-cadherin gene and hepatocarcinogenesis, and to assess its significance in clinical early diagnosis of hepatocellular carcinoma (HCC). MethodsSurgically resected specimens, among which cancerous and corresponding noncancerous liver tissues from 34 HCC patients, 10 liver cirrhosis from patients without HCC and normal liver tissues from 4 accidental deaths, were collected in West China Hospital. Breast cancer cell line MDA-MB-435 with promoter CpG islands hypermethylation of E-cadherin as positive control was gained from the Cell Bank of Chinese Academy of Sciences in Shanghai. The methylation status of promoter CpG island of E-cadherin gene was detected by nested methylationspecific polymerase chain reaction (nested-MSP). ResultsE-cadherin gene promoter CpG islands hypermethylation was found in 61.76% (21/34) of cancerous tissues, in 29.41% (10/34) of noncancereous tissues from the 34 HCC patients and in 50.00% (5/10) liver cirrhosis from patients without HCC. None of the 4 normal liver samples were detected E-cadherin mehylation positive. Moreover, the methylation of E-cadherin gene was significantly more frequent in 34 cancerous than that in corresponding noncancerous liver tissues (P lt;0.05), which had no significant difference between the 10 cirrhotic samples and cancerous or non-cancerous liver tissues (P gt;0.05). In 34 cancerous samples, with the combination of both biomarkers of E-cadherin methylation and AFP400 (serum AFP level at a cutoff of 400 μg/L), the diagnostic sensitivity of HCC increased to 82.35%. ConclusionsThe aberrant promoter methylation of E-cadherin gene may play a vital role in the development and progression of HCC. Moreover, it might be an early event in hepatocarcinogensis. It is of high value to make further study to confirm the significance of E-cadherin gene methylation in clinical diagnosis and therapy.

Citation： HUANG Wenqing ,YANG Wenli,CHAI Xinjuan,CHEN Kefei,WEI Ling,LI Bo,QIN Yang. Aberrant Promoter CpG Islands Methylation of E-cadherin in Human Primary Hepatocellular Carcinomas. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(5): 514-519. doi: Copy

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1. Song P, Tang W, Tamura S, et al. The management of hepatocellular carcinoma in Asia: a guideline combining quantitative and qualitative evaluation [J]. Biosci Trends, 2010, 4(6): 283287.
2. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002 [J]. CA Cancer J Clin, 2005, 55(2): 74108.
3. Lee TK, Castilho A, Ma S, et al. Liver cancer stem cells: implications for a new therapeutic target [J]. Liver Int, 2009, 29(7): 955965.
4. Nishida N, Nagasaka T, Nishimura T, et al. Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma [J]. Hepatology, 2008, 47(3): 908918.
5. Moribe T, Iizuka N, Miura T, et al. Methylation of multiple genes as molecular markers for diagnosis of a small, welldifferentiated hepatocellular carcinoma [J]. Int J Cancer, 2009, 125(2): 388397.
6. Celebiler Cavusoglu A, Sevinc AI, Saydam S, et al. Promoter methylation and expression changes of CDH1 and P16 genes in invasive breast cancer and adjacent normal breast tissue [J]. Neoplasma, 2010, 57(5): 465472.
7. Liu RY, Lei Z, Li W, et al. Infrequently methylated event at sites 181 to 9 within the 5′ CpG island of Ecadherin in nonsmall cell lung cancer [J]. Exp Lung Res, 2009, 35(7): 541553.
8. Yi TZ, Guo J, Zhou L, et al. Prognostic value of Ecadherin expression and CDH1 promoter methylation in patients with endometrial carcinoma [J]. Cancer Invest, 2011, 29(1): 8692.
9. Yamashita K, Sakuramoto S, Watanabe M. Genomic and epigenetic profiles of gastric cancer: potential diagnostic and therapeutic applications [J]. Surg Today, 2011, 41(1): 2438.
10. Yang X, Yan L, Davidson NE. DNA methylation in breast cancer [J]. Endocr Relat Cancer, 2001, 8(2): 115127.
11. Herman JG, Graff JR, Myhnen S, et al. Methylationspecific PCR: a novel PCR assay for methylation status of CpG islands [J]. Proc Natl Acad Sci U S A, 1996, 93(18): 98219826.
12. Guo M, Ren J, House MG, et al. Accumulation of promoter methylation suggests epigenetic progression in squamous cell carcinoma of the esophagus [J]. Clin Cancer Res, 2006, 12(15): 45154522.
13. Taniguchi K, Yamada T, Sasaki Y, et al. Genetic and epigenetic characteristics of human multiple hepatocellular carcinoma [J]. BMC Cancer, 2010, 10: 530.
14. Oh BK, Um TH, Choi GH, et al. Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis [J]. Int J Cancer, 2011, 128(4): 857868.
15. 车向明, 王曙逢, 樊林, 等. Ecadherin 反义寡核苷酸对肿瘤细胞浸润能力影响的研究 [J]. 中国普外基础与临床杂志, 2006,13(2): 191193.
16. 刘骅, 周敏, 赵文毅, 等. 不同压强与时程CO2气腹对胃癌细胞黏附侵袭能力的影响 [J]. 中国普外基础与临床杂志, 2010, 17(6): 557561.
17. Zhai B, Yan HX, Liu SQ, et al. Reduced expression of Ecadherin/catenin complex in hepatocellular carcinomas [J]. World J Gastroenterol, 2008, 14(37): 56655673.
18. 张友才, 陈金霞, 龚玲, 等. 肝细胞肝癌上皮钙黏素基因表达和启动子甲基化研究 [J]. 实用肿瘤杂志, 2008, 23(4): 314317.
19. Li B, Liu W, Wang L, et al. CpG island methylator phenotype associated with tumor recurrence in tumornodemetastasis stage Ⅰ hepatocellular carcinoma [J]. Ann Surg Oncol, 2010, 17(7): 19171926.
20. Wang J, Qin Y, Li B, et al. Detection of aberrant promoter methylation of GSTP1 in the tumor and serum of Chinese human primary hepatocellular carcinoma patients [J]. Clin Biochem, 2006, 39(4): 344348.
21. Tseng RC, Lee SH, Hsu HS, et al. SLIT2 attenuation during lung cancer progression deregulates betacatenin and Ecadherin and associates with poor prognosis [J]. Cancer Res, 2010, 70(2): 543551.
22. Du GS, Wang JM, Lu JX, et al. Expression of PaPKCiota, Ecadherin, and betacatenin related to invasion and metastasis in hepatocellular carcinoma [J]. Ann Surg Oncol, 2009, 16(6): 15781586.
23. Zhang XF, Qi X, Meng B, et al. Prognosis evaluation in alphafetoprotein negative hepatocellular carcinoma after hepatectomy: comparison of five staging systems [J]. Eur J Surg Oncol, 2010, 36(8): 718724.
24. Snowberger N, Chinnakotla S, Lepe RM, et al. Alpha fetoprotein, ultrasound, computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in patients with advanced cirrhosis [J]. Aliment Pharmacol Ther, 2007, 26(9): 11871194.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Aberrant Promoter CpG Islands Methylation of E-cadherin in Human Primary Hepatocellular Carcinomas

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