Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: clinical and histopathologic correlations
Loss of WW domain-containing oxidoreductase expression in the progression and development of gastric carcinoma: clinical and histopathologic correlations
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DOI：
10.1007/s00428-010-0956-y
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发表时间：
2010-10-01
期刊：
影响因子：
3.5
通讯作者：
Yokozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Maeda, Naoko;Semba, Shuho;Yokozaki, Hiroshi
本研究的目的是探讨位于常见脆性部位FRA16D(16q23.3-24.1)的WWOX抑癌基因在胃癌发生发展中的作用。我们检测了WWOX在胃癌细胞系和组织标本中的表达变化，以及WWOX基因在缺失WWOX的胃癌细胞中的修复作用。所有胃癌细胞系(HSC-45、HSC-57、HSC-59、MKN-7和MKN-74)均显示WWOX在mRNA和蛋白水平的表达降低，并在HSC-45和HSC-59细胞中检测到WWOX调控位点的高甲基化。有趣的是，用脱乙酰剂曲古菌素A和脱甲基剂5-氮杂-2‘-脱氧胞苷处理HSC-59细胞，恢复了内源性WWOX的表达水平。用Ad-WWOX将WWOX基因恢复到HSC-59细胞中，有效地抑制了细胞的生长，增加了亚G(1)DNA含量的细胞群体。在73例胃癌组织标本中，有24例(33%)检测到WWOX表达缺失，与WWOX调控位点的高甲基化一致。令人惊讶的是，WWOX免疫反应阴性与多种临床病理指标有关，包括组织学(P=0.0001)、侵袭深度(P=0.0004)、淋巴结转移(P=0.0003)、血管浸润性(淋巴管P=0.0167和静脉血管P=0.0005)和临床病理分期(P=0.001)。这些发现表明，WWOX表达的抑制可能在胃癌的发生中起重要作用。因此，WWOX似乎是分子诊断GCs恶性程度的一个很好的生物标志物。
The purpose of this study is to investigate the role of the WW domain-containing oxidoreductase (WWOX) tumor suppressor that maps to the common fragile site FRA16D (16q23.3-24.1) during the development of gastric carcinoma (GC), we examined the altered expression of WWOX in GC cell lines and tissue samples as well as the effects of restoration of the WWOX gene into WWOX-deficient GC cells. All GC cell lines (HSC-45, HSC-57, HSC-59, MKN-7, and MKN-74) showed reduced WWOX expression at the mRNA and protein levels and hypermethylation at the WWOX regulatory site was detected in HSC-45 and HSC-59 cells. Interestingly, treatment with the deacetylating agent trichostatin A and the demethylating agent 5-aza-2'-deoxycytidine restored endogenous WWOX expression levels in HSC-59 cells. Restoration of the WWOX gene with Ad-WWOX into HSC-59 cells effectively suppressed cell growth and increased the population of cells in subG(1) DNA content. In GC tissue samples, the loss of WWOX expression was detected in 24 (33%) of 73 GC cases in accordance with the hypermethylation at the WWOX regulatory site. Surprisingly, negative immunoreactivity against WWOX showed a significant relationship with several clinicopathologic findings, including histology (P = 0.0001), depth of invasion (P = 0.0004), lymph node metastasis (P = 0.0003), vessel infiltration (lymphatic vessels, P = 0.0167 and venous vessels, P = 0.0005), and clinicopathologic stage (P = 0.001). These findings suggest that repression of WWOX expression may play an important role in stomach carcinogenesis. WWOX thus appears to be a good biomarker for molecular diagnosis of the grade of malignancy of GCs.