Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer
Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer
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DOI：
10.1002/ijc.30286
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发表时间：
2016-11-15
影响因子：
6.4
通讯作者：
Kodera, Yasuhiro
中科院分区：
文献类型：
--
作者：
Kanda, Mitsuro;Tanaka, Chie;Kodera, Yasuhiro
根治性切除后肿瘤复发的预测对于确定胃癌（GC）患者的预后至关重要。 GC的发生和进展与胃粘膜慢性炎症引起的不适当的免疫反应有关。为了鉴定参与 GC 进展的免疫调节分子，对 GC 细胞系以及 200 对 GC 患者的肿瘤和正常组织进行了基因表达、扩增和甲基化以及差异表达基因的功能分析。转录组分析显示，与相应的正常胃粘膜相比，原代GC组织中边缘区B和B1细胞特异性蛋白（MZB1）的表达水平显着降低。 PCR 阵列分析探索与 MZB1 协同表达的基因，结果表明 GC 细胞系中 MZB1 mRNA 的差异表达与编码雌激素受体 1 和去苏酰肽酶 1 的 mRNA 水平呈正相关。在 MZB1 mRNA 水平降低的细胞系中，MZB1 启动子的高甲基化很常见。 siRNA 介导的 MZB1 敲除显着增加 GC 细胞系的增殖、侵袭和迁移。 MZB1 低表达是根治性胃切除术后复发的独立预后因素，并且与血行复发增加显着相关。 MZB1 作为 GC 的抑制剂。原发性 GC 组织中 MZB1 的低表达预示着治愈性切除后的复发。
Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analyzed for gene expression, amplification and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection.