Samsung Advanced Institute for Health Sciences and Technology, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Ewha Research Center for Systems Biology, Ewha Womans University, Seoul, Korea.
Gastroenterology. 2015 Jan;148(1):137-147.e9. doi: 10.1053/j.gastro.2014.09.020. Epub 2014 Sep 22.
BACKGROUND & AIMS: Patients with Epstein-Barr virus-associated gastric carcinoma (EBVaGC) have a better prognosis than those with gastric cancer not associated with EBV infection (EBVnGC). This is partly because EBV infection recruits lymphocytes, which infiltrate the tumor. A high degree of tumor heterogeneity is likely to be associated with poor response. We investigated differences in gene expression patterns between EBVaGC and EBVnGC.
We used gene expression profile analysis to compare tumor and nontumor gastric tissues from 12 patients with EBVaGC and 14 patients with EBVnGC. Findings were validated by whole transcriptome RNAseq and real-time quantitative polymerase chain reaction analyses. CD3(+) primary T cells were isolated from human blood samples; migration of these cells and of Jurkat cells were measured in culture with EBV-infected and uninfected gastric cancer cells.
Based on Pearson correlation matrix analysis, EBVaGCs had a higher degree of homogeneity than EBVnGCs. Although 4550 genes were differentially expressed between tumor and nontumor gastric tissues of patients with EBVnGC, only 186 genes were differentially expressed between tumor and nontumor gastric tissues of patients with EBVaGC (P < .001). This finding supports the concept that EBVaGCs have fewer genetic and epigenetic alterations than EBVnGCs. Expression of major histocompatibility complex class II genes and genes that regulate chemokine activity were more often deregulated in EBVaGCs compared with nontumor tissues. In culture, more T cells migrated to EBV-infected gastric cancer cells than to uninfected cells; migration was blocked with a neutralizing antibody against CXCR3 (a receptor for many chemokines).
Fewer genes are deregulated in EBVaGC than in EBVnGC. Most changes in EBVaGCs occur in immune response genes. These changes might allow EBVaGC to recruit reactive immune cells; this might contribute to the better outcomes of these patients compared with those with EBVnGC.
与 EBV 感染无关的胃癌（EBVnGC）患者的预后比 EBV 相关胃腺癌（EBVaGC）患者差。这在一定程度上是因为 EBV 感染募集了浸润肿瘤的淋巴细胞。肿瘤异质性程度高可能与应答不良有关。我们研究了 EBVaGC 和 EBVnGC 之间的基因表达模式差异。
我们使用基因表达谱分析比较了 12 例 EBVaGC 和 14 例 EBVnGC 患者的肿瘤和非肿瘤胃组织。通过全转录组 RNAseq 和实时定量聚合酶链反应分析验证了研究结果。从人血样中分离出 CD3(+)原代 T 细胞；在培养中，用 EBV 感染和未感染的胃癌细胞测量这些细胞和 Jurkat 细胞的迁移。
基于 Pearson 相关矩阵分析，EBVaGC 的同质性高于 EBVnGC。尽管 EBVnGC 患者肿瘤和非肿瘤胃组织之间有 4550 个基因差异表达，但 EBVaGC 患者肿瘤和非肿瘤胃组织之间仅有 186 个基因差异表达（P<0.001）。这一发现支持 EBVaGC 比 EBVnGC 具有更少的遗传和表观遗传改变的概念。与非肿瘤组织相比，EBVaGC 中主要组织相容性复合体 II 基因和调节趋化因子活性的基因表达更常失调。在培养中，与未感染细胞相比，更多的 T 细胞迁移到 EBV 感染的胃癌细胞；用针对许多趋化因子受体 CXCR3 的中和抗体阻断迁移。
EBVaGC 中失调的基因比 EBVnGC 少。EBVaGC 中的大多数变化发生在免疫反应基因中。这些变化可能使 EBVaGC 募集反应性免疫细胞；这可能有助于这些患者的预后优于 EBVnGC 患者。
