Frequent loss of Brm expression in gastric cancer correlates with histologic features and differentiation state
Frequent loss of Brm expression in gastric cancer correlates with histologic features and differentiation state
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DOI：
10.1158/0008-5472.can-07-2601
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
Iba, Hideo
中科院分区：
文献类型：
--
作者：
Yarnamichi, Nobutake;Inada, Ken-Ichi;Iba, Hideo
哺乳动物SWI/SNF染色质重塑复合物是一种重要的表观遗传调节因子，含有单个Brm或BRG 1分子作为其催化亚基。我们观察到在人胃癌细胞系中Brm表达频繁丢失，但BRG 1没有丢失。用组蛋白去乙酰化酶抑制剂治疗挽救了Brm表达，表明该基因的表观遗传调节，并且基于RNA干扰的集落形成测定揭示了Brm的抗癌特性。89例原发性胃癌中60例（67%）Brm免疫染色明显减弱。重度下降37例（42%）。Brm缺失在主要胃癌类型（高分化或中分化管状腺癌和低分化腺癌）中很常见，并且与未分化状态呈正相关。在较小的胃癌类型中，Brut表达在印戒细胞癌和粘液腺癌中持续存在，但在乳头状腺癌中观察到显著降低。肠上皮化生从未显示表达降低，表明Brm是胃癌发生的有效标志物。相反，BRG 1在大多数情况下保留;与其他恶性肿瘤相反，BRG 1和Brut的伴随损失在胃癌中很少见。我们进一步表明，Brm是绒毛蛋白表达所必需的，绒毛蛋白是肠上皮化生和分化的决定性标志物。通过调控这些对消化道分化起重要作用的基因，Brm可能在决定胃恶性肿瘤的组织学特征方面发挥重要作用。
The mammalian SWI/SNF chromatin remodeling complex, an essential epigenetic regulator, contains either a single Brm or BRG1 molecule as its catalytic subunit. We observed frequent loss of Brm expression but not of BRG1 in human gastric cancer cell lines. Treatment with histone deacetylase inhibitor rescued Brm expression, indicating epigenetic regulation of this gene, and an RNA interference-based colony formation assay revealed antioncogenic properties of Brm. Brm immunostaining of 89 primary gastric cancers showed an obvious reduction in 60 cases (67%). and a severe decrease in 37 cases (42%). Loss of Brm is frequent in the major gastric cancer types (well- or moderately-differentiated tubular adenocarcinoma and poorly-differentiated adenocarcinoma) and positively correlates with the undifferentiated state. Among the minor gastric cancer types, Brut expression persists in signet-ring cell carcinoma and mucinous adenocarcinoma, but a marked decrease is observed in papillary adenocarcinoma. Intestinal metaplasia never shows decreased expression, indicating that Brm is a valid marker of gastric oncogenesis. In contrast, BRG1 is retained in most cases; a concomitant loss of BRG1 and Brut is rare in gastric cancer, contrary to other malignancies. We further show that Brm is required for villin expression, a definitive marker of intestinal metaplasia and differentiation. Via regulating such genes important for gut differentiation, Brm should play significant roles in determining the histologic features of gastric malignancy.