结直肠癌细胞中 PTGER2 的过表达与微卫星不稳定性相关，与 CpG 岛甲基化表型无关。
PTGER2 overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype.
机构信息
Department of Medical Oncology, Dana-FarberCancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
出版信息
Cancer Epidemiol Biomarkers Prev. 2010 Mar;19(3):822-31. doi: 10.1158/1055-9965.EPI-09-1154. Epub 2010 Mar 3.
BACKGROUND
Prostaglandin-endoperoxide synthase 2 (PTGS2, the HUGO Gene Nomenclature Committee-approved official symbol for cycloxygenase-2, COX-2) and its enzymatic product prostaglandin E2 have critical roles in inflammation and carcinogenesis through the G protein-coupled receptor PTGER2 (EP2). The PTGS2 (COX-2) pathway is a promising target for cancer therapy and chemoprevention. PTGS2 (COX-2) expression in colon cancer has been inversely associated with survival as well as tumoral microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). However, the prognostic significance of PTGER2 expression or its relationship with MSI, CIMP, LINE-1 hypomethylation, or PTGS2 (COX-2) remains uncertain.
METHODS
Using the database of 516 colorectal cancers in two prospective cohort studies with clinical outcome data, we detected PTGER2 overexpression in 169 (33%) tumors by immunohistochemistry. We analyzed MSI using 10 microsatellite markers; CIMP by MethyLight (real-time methylation-specific PCR) on an eight-marker panel [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1]; BRAF, KRAS, PIK3CA, and methylation in LINE-1 by Pyrosequencing; and CTNNB1 (beta-catenin) and TP53 (p53) by immunohistochemistry.
RESULTS
PTGER2 overexpression was positively associated with the mucinous component (P = 0.0016), signet ring cells (P = 0.0024), CIMP-high (P = 0.0023), and MSI-high (P < 0.0001). In multivariate analysis, the significant relationship between PTGER2 and MSI-high persisted (adjusted odds ratio, 2.82; 95% confidence interval, 1.69-4.72; P < 0.0001). PTGER2 was not significantly associated with PTGS2 (COX-2), TP53, or CTNNB1 expression, patient survival, or prognosis.
CONCLUSION
PTGER2 overexpression is associated with MSI-high in colorectal cancer.
IMPACT
Our data imply potential roles of inflammatory reaction by PTGER2 upregulation in carcinogenic process to MSI-high colorectal cancer.
背景
前列腺素内过氧化物合酶 2（PTGS2，即 HUGO 基因命名委员会批准的环氧化酶-2 的官方符号，COX-2）及其酶产物前列腺素 E2 通过 G 蛋白偶联受体 PTGER2（EP2）在炎症和癌变中发挥关键作用。PTGS2（COX-2）途径是癌症治疗和化学预防的有前途的靶点。结肠癌中 PTGS2（COX-2）的表达与生存以及肿瘤微卫星不稳定性（MSI）和 CpG 岛甲基化表型（CIMP）呈负相关。然而，PTGER2 表达的预后意义及其与 MSI、CIMP、LINE-1 低甲基化或 PTGS2（COX-2）的关系仍不确定。
方法
使用包含临床结局数据的两项前瞻性队列研究中的 516 例结直肠癌数据库，我们通过免疫组织化学检测到 169 例（33%）肿瘤中 PTGER2 过表达。我们使用 10 个微卫星标记物分析 MSI；通过 MethyLight（实时甲基化特异性 PCR）在 8 个标记物组 [CACNA1G、CDKN2A（p16）、CRABP1、IGF2、MLH1、NEUROG1、RUNX3 和 SOCS1] 上分析 CIMP；通过焦磷酸测序分析 BRAF、KRAS、PIK3CA 和 LINE-1 中的甲基化；通过免疫组织化学分析 CTNNB1（β-连环蛋白）和 TP53（p53）。
结果
PTGER2 过表达与粘液成分呈正相关（P = 0.0016）、印戒细胞（P = 0.0024）、CIMP-高（P = 0.0023）和 MSI-高（P < 0.0001）。多变量分析表明，PTGER2 与 MSI-高之间的显著关系仍然存在（调整后的优势比，2.82；95%置信区间，1.69-4.72；P < 0.0001）。PTGER2 与 PTGS2（COX-2）、TP53 或 CTNNB1 表达、患者生存或预后无显著相关性。
结论
PTGER2 过表达与结直肠癌中的 MSI-高相关。
影响
我们的数据表明，PTGER2 上调引起的炎症反应可能在致癌过程中导致 MSI-高的结直肠癌。
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