DNA demethylation of Vascular endothelial growth factor-C is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer
DNA demethylation of Vascular endothelial growth factor-C is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer
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DOI：
10.1002/ijc.22433
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发表时间：
2007-04-15
影响因子：
6.4
通讯作者：
Yasui, Wataru
中科院分区：
文献类型：
--
作者：
Matsumura, Shunji;Oue, Naohide;Yasui, Wataru
已有研究表明，实体瘤中的淋巴管生成与淋巴转移有关。血管内皮生长因子（VEGF）-C的过表达在癌症的淋巴管生成中起主要作用。在本研究中，VEGF-C基因的DNA甲基化和表达的胃癌（GC）进行了研究。4种胃癌细胞系（MKN-45、MKN-74、HSC-39和HSC-43）均不表达VEGF-C，且VEGF-C基因在这些细胞中被甲基化。相反，7个GC细胞系（MKN-1、MKN-7、MKN-28、TMK-1、KATO-III、SH 101-P4和HSC-44 PE）表达VEGF-C，并且发现在这些细胞系中VEGF-C基因未甲基化。此外，VEGF-C mRNA的表达通过用去甲基化剂Aza-2 '-脱氧胞苷处理而恢复。在GC组织样本中，亚硫酸氢盐DNA测序分析显示，VEGF-C在31个GC样本中的9个（29.0%）中未甲基化，而在相应的非肿瘤性粘膜样本中未观察到去甲基化。用定量逆转录聚合酶链反应（RT-PCR）检测31例胃癌中16例（51.6%）VEGF-C mRNA的表达。9例VEGF-C去甲基化的胃癌中，8例（88.9%）VEGF-C过表达。相反，在22例无VEGF-C去甲基化的胃癌病例中，8例（36.4%）VEGF-C过表达（p = 0.0155）。此外，胃癌组织中通过podoplanin免疫染色确定的淋巴管密度与VEGF-C的过表达相关（p < 0.0001）。这些结果表明，去甲基化和激活的VEGF-C基因可能参与淋巴管生成在GC。(c)2007 Wiley-Liss，Inc.
Previous studies have indicated that lymphangiogenesis in solid tumors is associated with lymphatic metastasis. Overexpression of Vascular endothelial growth factor (VEGF)-C plays a major role in lymphangiogenesis in cancers. In the present study, DNA methylation and expression of the VEGF-C gene was investigated in gastric cancer (GC). Four GC cell lines (MKN-45, MKN-74, HSC-39 and HSC-43) showed no expression of VEGF-C, and the VEGF-C gene was found to be methylated in these cells. In contrast, 7 GC cell lines (MKN-1, MKN-7, MKN-28, TMK-1, KATO-III, SH101-P4 and HSC-44PE) expressed VEGF-C, and the VEGF-C gene was found to be unmethylated in these cell lines. In addition, expression of VEGF-C mRNA was retrieved by treatment with a demethylating agent, Aza-2'-deoxycytidine. In GC tissue samples, bisultite DNA sequencing analysis revealed that VEGF-C was not methylated in 9 (29.0%) of 31 GC samples, whereas demethylation was not observed in corresponding non-neoplastic mucosa samples. Overexpression of VEGF-C mRNA was observed in 16 (51.6%) of 31 GC samples by quantitative reverse transcriptionpolymerase chain reaction. Of the 9 GC cases with VEGF-C demethylation, 8 (88.9%) overexpressed VEGF-C. In contrast, of the 22 GC cases without VEGF-C demethylation, 8 (36.4%) overexpressed VEGF-C (p = 0.0155). Furthermore, lymphatic vessel density determined by immunostaining of podoplanin in GC tissues was associated with overexpression of VEGF-C (p < 0.0001). These results suggest that demethylation and activation of the VEGF-C gene is likely involved in lymphangiogenesis in GC. (c) 2007 Wiley-Liss, Inc.