Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer
Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer
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DOI：
10.1093/carcin/bgi045
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发表时间：
2005-06-01
期刊：
影响因子：
4.7
通讯作者：
Reid, KBM
中科院分区：
文献类型：
--
作者：
Kang, WQ;Nielsen, O;Reid, KBM
DMBT 1（在恶性脑肿瘤中缺失1）表达的缺失与消化道食管癌、胃癌和结直肠癌的发生有关，但其潜在机制尚不清楚。在本研究中，使用胃细胞系AGS，我们确定了两个细胞内信号分子蛋白激酶C（PKC）和细胞外信号相关激酶（ERK）。他们介导的佛波醇肉豆蔻酸酯醋酸酯（PMA）下调DMBT 1的表达和细胞分化的启动，这是通过细胞周期的撤退和诱导的组织特异性标记三叶因子1（TFF 1）。时程研究表明，PMA激活ERK激酶后，在同一时间点检测到TFF 1的诱导和DMBT 1的减少。然后，我们证明了最低水平的DMBT 1在增殖的AGS细胞接种在低密度，ERK活性高。通过CFSE标记判断，ERK抑制剂PD 98059或高密度接种降低ERK活性显著降低AGS细胞生长。这种细胞效应是由细胞周期蛋白D/p21（Cip/Waf 1）和G（0）/G（1）阻滞引起的，并伴随着DMBT 1表达细胞的显著增加。最后，我们发现，针对DMBT 1的siRNA对诱导细胞生长停滞标志物肠道富集的Kruppel样因子（GKLF）没有影响，但减少了TFF 1的PMA诱导。沿着其上调与G（0）/G（1）阻滞相一致，以及其在分化细胞中的减弱，这些结果表明DMBT 1的瞬时诱导在胃上皮分化样过程的早期阶段是明显特异的，此时它可能在细胞命运决定中起作用。与这种潜在的功能相一致，我们在人胃腺癌标本中检测到DMBT 1表达的频繁异常。
Abnormalities in the expression of DMBT1 (deleted in malignant brain tumors 1) have been implicated in the development of esophageal, gastric and colorectal cancers of the alimentary tract, but the underlying mechanism remains unclear. In the present study, using the gastric cell line AGS, we identified two intracellular signaling molecules protein kinase C (PKC) and extracellular signal-related kinase (ERK). They mediated both the phorbol myristate acetate (PMA) downregulation of DMBT1 expression and the initiation of cell differentiation, which was measured by cell cycle withdrawal and the induction of the tissue-specific marker trefoil factor 1 (TFF1). A time-course study showed that following the PMA activation of ERK kinase, the induction of TFF1 and the reduction of DMBT1 were detected at the same time point. We then demonstrated a minimal level of DMBT1 in proliferating AGS cells seeded at low density, where ERK activity was high. Reduction of ERK activity, either by an ERK inhibitor PD98059 or by high-density seeding, significantly reduced AGS cell growth judged by CFSE labeling. This cellular effect was elicited by cyclin D/p21 (Cip/Waf1) and G(0)/G(1) arrest, and was accompanied by a marked increase in DMBT1-expressing cells. Finally, we showed that siRNA directed against DMBT1 had no effect on the induction of a cell growth arrest marker, gut-enriched Kruppel-like factor (GKLF), but reduced the PMA induction of TFF1. Along with its upregulation coinciding with G(0)/G(1) arrest, and its attenuation in differentiated cells, these results suggest that the transient induction of DMBT1 is apparently specific at an early stage of gastric epithelial differentiation-like process, when it may play a role in cell fate decision. Consistent with such a potential function, we detected frequent abnormalities of the DMBT1 expression in the specimens of human gastric adenocarcinoma.