Wang Ya-Wen, Chen Xu, Gao Ji-Wei, Zhang Hui, Ma Ran-Ran, Gao Zu-Hua, Gao Peng
Department of Pathology, School of Medicine, Shandong University, Jinan, P.R. China.
Department of Pathology, McGill University, Montreal, Canada.
Oncotarget. 2015 Apr 30;6(12):10646-57. doi: 10.18632/oncotarget.3392.
cAMP responsive element binding protein 1 (CREB1) has been reported to be implicated in tumor development and progression of human cancers. However, the clinical significance and regulatory mechanisms of CREB1 expression in gastric cancer remain largely unknown. In the present study, immunohistochemistry was performed to detect the expression of CREB1 protein in 185 primary gastric cancer tissues, 50 secondary lymph node metastatic foci and 50 nontumorous gastric tissues. A prognostic model combining CREB1 expression with TNM tumor stage was constructed by logistic regression analysis. Regulation of CREB1 by miRNAs was investigated by luciferase reporter assay and Western blot. It was shown that CREB1 was highly expressed and correlated with lymph node metastasis, distant metastasis and tumor stage and poor outcome in gastric cancer. The prognostic model was proven to be an independent prognosis predictor and performed better than CREB1 or tumor stage alone. CREB1 was identified as a direct target of miR-27b and miR-200b, and down-regulated by miR-27b/miR-200b. We conclude that CREB1 is a promising biomarker to predict tumor metastasis and patient outcome in gastric cancer, and the miR-27b/miR-200b-CREB1 pathway may serve as a potential molecular target for the treatment of gastric cancer.
据报道，环磷酸腺苷反应元件结合蛋白1（CREB1）与人类癌症的肿瘤发生和进展有关。然而，CREB1在胃癌中的临床意义和调控机制仍 largely unknown。在本研究中，采用免疫组织化学方法检测185例原发性胃癌组织、50例继发性淋巴结转移灶和50例非肿瘤性胃组织中CREB1蛋白的表达。通过逻辑回归分析构建了将CREB1表达与TNM肿瘤分期相结合的预后模型。通过荧光素酶报告基因检测和蛋白质印迹法研究了miRNA对CREB1的调控。结果表明，CREB1在胃癌中高表达，与淋巴结转移、远处转移、肿瘤分期及预后不良相关。该预后模型被证明是一个独立的预后预测指标，其表现优于单独的CREB1或肿瘤分期。CREB1被确定为miR-27b和miR-200b的直接靶点，并被miR-27b/miR-200b下调。我们得出结论，CREB1是预测胃癌肿瘤转移和患者预后的一个有前景的生物标志物，miR-27b/miR-200b-CREB1通路可能作为治疗胃癌的潜在分子靶点。
