Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Tanaka Haruyoshi, Shimizu Dai, Shibata Masahiro, Takami Hideki, Hayashi Masamichi, Iwata Naoki, Niwa Yukiko, Yamada Suguru, Fujii Tsutomu, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro
Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
Int J Cancer. 2016 Nov 15;139(10):2290-8. doi: 10.1002/ijc.30286. Epub 2016 Aug 6.
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.
预测胃癌（GC）患者根治性切除术后的肿瘤复发对于判断其预后至关重要。GC的发生和进展与胃黏膜慢性炎症引起的不适当免疫反应有关。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患者的肿瘤组织和正常组织进行了基因表达、扩增和甲基化分析以及一个差异表达基因的功能分析。转录组分析显示，与相应的正常胃黏膜相比，边缘区B细胞和B1细胞特异性蛋白（MZB1）在原发性GC组织中的表达水平显著降低。探索与MZB1协同表达基因的PCR阵列分析表明，GC细胞系中MZB1 mRNA的差异表达与编码雌激素受体1和去SUMO化异肽酶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敲低显著增加了GC细胞系的增殖、侵袭和迁移。低MZB1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著相关。MZB1作为GC的抑制因子。原发性GC组织中低MZB1表达可预测根治性切除术后的复发。
