STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers.
STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers.
复制标题
DOI：
10.1158/1078-0432.ccr-10-2694
复制
发表时间：
2011-03-15
期刊：
影响因子：
--
通讯作者：
Ogino S
中科院分区：
文献类型：
--
作者：
Morikawa T;Baba Y;Yamauchi M;Kuchiba A;Nosho K;Shima K;Tanaka N;Huttenhower C;Frank DA;Fuchs CS;Ogino S
STAT3（信号转导子和转录激活子 3）是一种在某些癌症中持续激活的转录因子。 STAT3似乎在肿瘤微环境中的细胞增殖和存活、血管生成、促肿瘤炎症和抑制抗肿瘤宿主免疫反应中发挥着至关重要的作用。尽管STAT3信号通路是潜在的药物靶点，但STAT3激活的结直肠癌的临床、病理、分子或预后特征仍不确定。利用 724 例结肠癌和直肠癌病例的数据库，我们通过免疫组织化学评估了磷酸化 STAT3 (p-STAT3) 的表达。 Cox比例风险模型用于计算死亡风险比（HR），调整临床、病理和分子特征，包括微卫星不稳定性（MSI）、CpG岛甲基化表型（CIMP）、LINE-1甲基化、18q杂合性丢失、TP53（p53）、CTNNB1（β-连环蛋白）、JC病毒 T 抗原以及 KRAS、BRAF 和 PIK3CA 突变。在724个肿瘤中，131个（18%）显示高水平p-STAT3表达（p-STAT3-high），244个（34%）显示低水平表达（p-STAT3-low），其余349个（48%）p-STAT3阴性。 p-STAT3 过表达与显着较高的结直肠癌特异性死亡率相关 [log-rank p=0.0020；单变量 HR（p-STAT3-高 vs. p-STAT3-阴性）1.85，95% 置信区间 (CI) 1.30–2.63，Ptrend =0.0005；多变量 HR，1.61，95% CI 1.11–2.34，Ptrend =0.015）。 p-STAT3 表达与瘤周淋巴细胞反应呈正相关（多变量比值比 3.23；95% CI，1.89–5.53；p<0.0001）。 p-STAT3 表达与 MSI、CIMP 或 LINE-1 低甲基化无关。结直肠癌中的 STAT3 激活与不良临床结果相关，支持其作为预后生物标志物以及化学预防和/或治疗靶点的潜在作用。
STAT3 (signal transducer and activator of transcription 3) is a transcription factor that is constitutively activated in some cancers. STAT3 appears to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation and suppression of anti-tumor host immune response in the tumor microenvironment. Although the STAT3 signaling pathway is a potential drug target, clinical, pathologic, molecular or prognostic features of STAT3-activated colorectal cancer remain uncertain. Utilizing a database of 724 colon and rectal cancer cases, we evaluated phosphorylated STAT3 (p-STAT3) expression by immunohistochemistry. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical, pathologic and molecular features, including microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, 18q loss of heterozygosity, TP53 (p53), CTNNB1 (β-catenin), JC virus T-antigen, and KRAS, BRAF, and PIK3CA mutations. Among the 724 tumors, 131 (18%) showed high-level p-STAT3 expression (p-STAT3-high), 244 (34%) showed low-level expression (p-STAT3-low), and the remaining 349 (48%) were negative for p-STAT3. p-STAT3 overexpression was associated with significantly higher colorectal cancer-specific mortality [log-rank p=0.0020; univariate HR (p-STAT3-high vs. p-STAT3-negative) 1.85, 95% confidence interval (CI) 1.30–2.63, Ptrend =0.0005; multivariate HR, 1.61, 95% CI 1.11–2.34, Ptrend =0.015). p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate odds ratio 3.23; 95% CI, 1.89–5.53; p<0.0001). p-STAT3 expression was not associated with MSI, CIMP, or LINE-1 hypomethylation. STAT3 activation in colorectal cancer is associated with adverse clinical outcome, supporting its potential roles as a prognostic biomarker and a chemoprevention and/or therapeutic target.