GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling
GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling
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DOI：
10.1038/sj.onc.1210475
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发表时间：
2007-10-01
期刊：
影响因子：
8
通讯作者：
Sasaki, H.
中科院分区：
文献类型：
--
作者：
Saeki, N.;Kim, D. H.;Sasaki, H.
定义上皮细胞凋亡调节级联对于理解癌变很重要，因为癌细胞被认为是级联崩溃的结果。我们之前报道了一种新的基因GASDERMIN （GSDM）在胃中表达，但在胃癌细胞系中被抑制。此外，在本研究中，我们证实GSDM在胃上皮分泌粘液的凹细胞中表达，并且在原发性胃癌中经常沉默。我们发现GSDM具有高度的凋亡活性，其表达受转录因子LIM结构域1 （LMO1）的调控，通过runt相关转录因子3 （RUNX3）在GSDM启动子区域结合的序列。我们观察到GSDM与LMO1、RUNX3和II型转化生长因子- β受体（tgf - β RII）在pit细胞中共表达，发现tgf - β上调胃上皮细胞系中LMO1-和GSDM的表达并诱导细胞凋亡，通过分别抑制LMO1-、RUNX3-和GSDM的表达抑制细胞凋亡的结果证实了这一点。目前的数据表明，tgf - β、LMO1，可能还有RUNX3和GSDM形成了一条指导坑细胞凋亡的调控途径。
Defining apoptosis-regulatory cascades of the epithelium is important for understanding carcinogenesis, since cancer cells are considered to arise as a result of the collapse of the cascades. We previously reported that a novel gene GASDERMIN (GSDM) is expressed in the stomach but suppressed in gastric cancer cell lines. Furthermore, in this study, we demonstrated that GSDM is expressed in the mucus-secreting pit cells of the gastric epithelium and frequently silenced in primary gastric cancers. We found that GSDM has a highly apoptotic activity and its expression is regulated by a transcription factor LIM domain only 1 (LMO1) through a sequence to which Runt-related transcription factor 3 (RUNX3) binds, in a GSDM promoter region. We observed coexpression of GSDM with LMO1, RUNX3 and type II transforming growth factor-beta receptor (TGF-beta RII) in the pit cells, and found that TGF-beta upregulates the LMO1- and GSDM-expression in the gastric epithelial cell line and induces apoptosis, which was confirmed by the finding that the apoptosis induction is inhibited by suppression of each LMO1-, RUNX3- and GSDM expression, respectively. The present data suggest that TGF-beta, LMO1, possibly RUNX3, and GSDM form a regulatory pathway for directing the pit cells to apoptosis.