Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan,
Gastric Cancer. 2015 Apr;18(2):288-96. doi: 10.1007/s10120-014-0372-0. Epub 2014 Apr 3.
Patients with advanced gastric cancer (GC) have an adverse prognosis even after curative resection. Development of novel diagnostic and therapeutic approaches for GC is urgently required.
The expression and methylation status of DENN/MADD domain-containing protein 2D (DENND2D), a member of the membrane trafficking proteins, were evaluated in 12 GC cell lines and 112 pairs of surgical specimens. Subgroup analysis based on tumor differentiation, location, and morphology was also performed. Expression and distribution of DENND2D protein were determined by immunohistochemistry.
The majority of GC cell lines (75%) and tissues (79%) showed reduced expression of DENND2D mRNA compared with noncancerous gastric tissues. GC tissues showed a significantly lower mean expression level of mRNA and a higher frequency of promoter hypermethylation of DENND2D than corresponding noncancerous tissues. No significant differences in DENND2D mRNA expression and methylation status were found between GC subtypes categorized by tumor differentiation, location, and morphology. The expression patterns of DENND2D protein were confirmed to be consistent with those of DENND2D mRNA. Downregulation of DENND2D mRNA in GC tissues was significantly associated with factors related to more advanced GC and subsequent adverse prognosis. Among 72 patients who underwent R0 resection, downregulation of DENND2D mRNA in GC tissues was an independent prognostic factor and associated with early recurrence.
Our results suggested that DENND2D is a putative tumor suppressor gene regulated by promoter hypermethylation in GC. Downregulation of DENND2D can serve as a novel tumor biomarker to predict progression and early recurrence of all types of GC.
即使在根治性切除术后，晚期胃癌（GC）患者的预后仍较差。因此，迫切需要开发新的诊断和治疗 GC 的方法。
评估了膜转运蛋白成员 DENN/MADD 结构域包含蛋白 2D（DENND2D）在 12 种 GC 细胞系和 112 对手术标本中的表达和甲基化状态。还根据肿瘤分化、位置和形态进行了亚组分析。通过免疫组织化学测定 DENND2D 蛋白的表达和分布。
与非癌性胃组织相比，大多数 GC 细胞系（75%）和组织（79%）的 DENND2D mRNA 表达降低。GC 组织的 DENND2D mRNA 表达水平明显较低，启动子超甲基化频率也较高。GC 亚型根据肿瘤分化、位置和形态分类，DENND2D mRNA 表达和甲基化状态无显著差异。DENND2D 蛋白的表达模式与 DENND2D mRNA 的表达模式一致。GC 组织中 DENND2D mRNA 的下调与与更晚期 GC 相关的因素以及随后的不良预后显著相关。在接受 R0 切除的 72 例患者中，GC 组织中 DENND2D mRNA 的下调是独立的预后因素，与早期复发有关。
我们的研究结果表明，DENND2D 是 GC 中受启动子甲基化调控的假定肿瘤抑制基因。DENND2D 的下调可作为一种新的肿瘤标志物，预测所有类型 GC 的进展和早期复发。
