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中华普通外科学文献(电子版)

中华普通外科学文献(电子版) ›› 2015, Vol. 09 ›› Issue (04) : 261 -266. doi: 10.3877/cma.j.issn.1674-0793.2015.04.002

所属专题： 文献；

论著

DNA甲基化转移酶1/3b与肝癌临床病理特征和预后相关性研究
方钦亮1, 谢程融1, 赵文秀1, 孙红光1, 尹毅锐1, 张盛1, 王付强1, 彭友缘1, 王效民1, 尹震宇1,†()   
  1. 1. 361004　厦门大学附属中山医院肝胆外科　福建省慢性肝病肝癌重点实验室
  • 收稿日期:2015-02-05 出版日期:2015-08-01
  • 通信作者: 尹震宇
  • 基金资助:
    国家自然科学基金资助项目(81172286)

Correlation between DNMT1/3b and the clinicopathology and prognosis of hepatocellular carcinoma

Qinliang Fang1, Chengrong Xie1, Wenxiu Zhao1, Hongguang Sun1, Yirui Yin1, Sheng Zhang1, Fuqiang Wang1, Youyuan Peng1, Xiaomin Wang1, Zhenyu Yin1,†()   

  1. 1. Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatoce- llular Carcinoma, 361004 Xiamen, China
  • Received:2015-02-05 Published:2015-08-01
  • Corresponding author: Zhenyu Yin
  • About author:
    Corresponding author: Yin Zhenyu, Email:
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引用本文：

方钦亮, 谢程融, 赵文秀, 孙红光, 尹毅锐, 张盛, 王付强, 彭友缘, 王效民, 尹震宇. DNA甲基化转移酶1/3b与肝癌临床病理特征和预后相关性研究[J]. 中华普通外科学文献(电子版), 2015, 09(04): 261-266.

Qinliang Fang, Chengrong Xie, Wenxiu Zhao, Hongguang Sun, Yirui Yin, Sheng Zhang, Fuqiang Wang, Youyuan Peng, Xiaomin Wang, Zhenyu Yin. Correlation between DNMT1/3b and the clinicopathology and prognosis of hepatocellular carcinoma[J]. Chinese Archives of General Surgery(Electronic Edition), 2015, 09(04): 261-266.

目的

探讨DNA甲基化转移酶1/3b(DNMT1/3b)表达异常与肝癌临床病理特征和患者术后生存之间的相关性。

方法

采用免疫组织化学技术检测89例手术切除肝癌组织中DNMT1和DNMT3b的蛋白表达情况,结合临床病理及无瘤生存期和总生存期,分析DNMT1/3b与临床病理参数、预后的相关性,并通过高通量基因芯片技术筛选肝癌相关DNMT1和DNMT3b的靶基因。

结果

89例肝癌组织中DNMT1和DNMT3b皆为阳性63例,皆为阴性5例,单一阳性的分别为9例和12例。DNMT1/3b在肝癌组织中高表达与患者血清AFP(χ2=12.903,P=0.005)、乙型肝炎(χ2=9.535,P=0.023)、卫星灶(χ2=9.574,P=0.023)和肿瘤复发、转移及生存期有关,而与性别、肿瘤大小、肝硬化和肿瘤分化无关;Kaplan-Meier分析显示DNMT1/3b阳性组患者生存时间较阴性组短,差异有统计学意义(P<0.05)。高通量基因组甲基化芯片技术筛选出肝癌细胞中受DNMT1和DNMT3b调控的基因2 000多个,其中参与肿瘤侵袭转移的靶基因有112个。

结论

DNMT1/3b在肝癌组织中高表达与患者血清AFP、乙型肝炎、卫星灶和肿瘤复发、转移等临床病理特征和生存期密切相关,并可能通过调控多方面肿瘤相关基因促进肝癌复发、转移等恶性表型。

关键词: 肝癌, DNA甲基化转移酶, 生存期, 甲基化芯片
Objective

To detect the protein expression of DNMT1 and DNMT3b, and to explore the association of DNMT1/3b with the clinicopathology and prognosis of hepatocellular carcinoma.

Methods

Eighty-nine cases of hepatocellular carcinoma were detected by immunohistochemistry (IHC) for analysis of the correlation between DNMT1/3b expression and clinicopathologic parameters and the tumor-free survival and overall survival. And high-throughput gene chip technology was used to screen out DNMT1 and DNMT3b target genes.

Results

Both DNMT1 and DNMT3b expressions existed in 63 cases while 5 cases had neither DNMT1 nor DNMT3b. Nine cases had positive DNMT1 and 12 had positive DNMT3b. High level expression of DNMT1/3b was associated with serum AFP (χ2=12.903, P=0.005), HBV (χ2=9.535, P=0.023), satellite opacities (χ2=9.574, P=0.023), tumor recurrence and metastasis, and overall survival. No association was found with sex, size of tumor, liver cirrhosis and tumor differentiation. By Kaplan-Meier analysis, survival time was shorter in the patients with DNMT1 and/or 3b overexpression than in those with negative DNMT1 and 3b. More than 2 000 DNMT1 and DNMT3b target genes were screened out through high-throughput gene chip technology, and 112 of which were involved in tumor invasion and metastasis.

Conclusions

The overexpression of DNMT1 and DNMT3b are significantly related to the clinical and pathological characteristics such as serum AFP, HBV, satellite opacities, tumor recurrence and metastasis, and survival rate in hepatocellular carcinoma, and they can regulate a various tumor related genes in promoting the malignant phenotype including recurrence and metastasis of hepatocellular carcinoma.

Key words: Hepatocellular carcinoma, DNA methyltransferases, Survival rate, Methylation microarrays
表1 DNNT1和DNMT3b蛋白表达与肝癌患者临床病理特征的关系(例)
临床病理特征 DNMT1/3b蛋白表达(例数) χ2值 P值
(-/-) (+/-) (-/+) (+/+)
性别 ? ? ? ? 0.469 0.926
? 男 4 8 11 55 ? ?
? 女 1 1 1 8 ? ?
HBsAg ? ? ? ? 9.535 0.023
? 阳性 2 9 8 53 ? ?
? 阴性 3 0 4 10 ? ?
血清AFP(μg/L) ? ? ? ? 12.903 0.005
? <25 5 2 5 16 ? ?
? ≥25 0 7 7 47 ? ?
肿瘤大小(cm) ? ? ? ? 0.167 0.983
? <5 2 4 5 24 ? ?
? ≥5 3 5 7 39 ? ?
肝硬化 ? ? ? ? 1.053 0.788
? 阳性 2 4 6 36 ? ?
? 阴性 3 5 6 27 ? ?
肿瘤分化 ? ? ? ? 2.491 0.870
? 低 1 2 2 8 ? ?
? 中 3 5 9 50 ? ?
? 高 1 2 1 5 ? ?
卫星灶 ? ? ? ? 9.574 0.023
? 阳性 0 1 1 7 ? ?
? 阴性 5 8 11 57 ? ?
图1 免疫组织化学法检测89例HCC患者手术切除组织(包括癌组织T及癌旁组织NT)中DNMT1/3b的表达（×200）
图2 HCC患者DNMT1/DNMT3b的表达与预后的相关性分析
表2 112个肿瘤侵袭、转移相关基因中甲基化程度最高的前20个基因
染色体 甲基化得分 基因名称 基因库编码 编码蛋白名称
chr15 4.59 CTSH NM_004390 cathepsin H isoform a preproprotein
chr1 3.74 FOXE3 NM_012186 forkhead box E3
chr15 3.71 TYRO3 NM_006293 TYRO3 protein tyrosine kinase precursor
chr20 3.70 PARD6B NM_032521 PAR-6 beta
chr3 3.63 PODXL2 NM_015720 podocalyxin-like 2 precursor
chr16 3.63 SOX8 NM_014587 SRY (sex determining region Y)-box 8
chr17 3.61 ABR NM_021962 active breakpoint cluster region-related
chrX 3.60 SHROOM2 NM_001649 apical protein of Xenopus-like
chr8 3.52 DLC1 NM_006094 deleted in liver cancer 1 isoform 2
chr8 3.52 PTK2B NM_004103 PTK2B protein tyrosine kinase 2 beta isoform a
chr4 3.49 PITX2 NM_153427 paired-like homeodomain transcription factor 2
chr6 3.44 SRF NM_003131 serum response factor (c-fos serum response
chr11 3.39 P2RY2 NM_176071 purinergic receptor P2Y2
chr2 3.35 NCK2 NM_003581 NCK adaptor protein 2 isoform A
chr17 3.28 ACE NM_000789 angiotensin I converting enzyme 1 isoform 1
chr7 3.23 FSCN1 NM_003088 fascin 1
chr1 3.22 ARHGEF16 NM_014448 Rho guanine exchange factor 16
chr17 3.20 CDK5R1 NM_003885 cyclin-dependent kinase 5, regulatory subunit 1
chr9 3.19 NTRK2 NM_001007097 neurotrophic tyrosine kinase, receptor, type 2
chr20 3.14 SOX18 NM_018419 SRY-box 18
图3 肝癌细胞表型相关特点中受DNMT1/3b调控的基因分类数量
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