Sheng Wei-wei, Dong Ming, Zhou Jian-ping, Liu Qing-feng, Li Xin, Dong Qi
Department of Gastrointestinal Surgery, the First Hospital of China Medical University, Shenyang 110001, China.
Email:
Zhonghua Wai Ke Za Zhi. 2013 Oct;51(10):916-21.
To study the clinicopathological significance and relationship of Gli1, MDM2 and p53 expression in human pancreatic cancer.
The expression of Gli1, MDM2 and p53 proteins in 57 paired paraffin embedded pancreatic ductal adenocarcinoma (PDAC) specimens and adjacent non-cancerous pancreatic tissues was detected by immunohistochemistry. The relationship between their expression and clinicopathological characters was analyzed. Quantitative real-time PCR (qRT-PCR) was used to examine the expression of Gli1 mRNA level in 14 paired fresh PDAC specimens and adjacent non-cancerous pancreatic tissues. siRNA interference were used to further detect the close relationship among them.
IHC showed the expression of Gli1 (50.9%), MDM2 (57.9%) and p53 (56.1%) was increased in 57 cases of pancreatic cancer compared to that in paired normal pancreatic tissues (33.3%, 26.3% and 17.5% respectively, t = 2.413, 2.848 and 2.960, all P < 0.05). Gli1 expression was positively associated with tumor TNM stage (χ(2) = 8.211, P = 0.004), invasion depth (χ(2) = 4.247, P = 0.039) and MDM2 expression (r = 0.299, χ(2) = 5.105, P = 0.024), while expression of MDM2 and p53 was associated with tumor invasion depth (χ(2) = 5.182, P = 0.023) and TNM stage (χ(2) = 5.696, P = 0.017), respectively. Univariate and multivariate analysis revealed that Gli1 was an independent adverse prognostic indicator for patients with PDAC (RR = 2.290, 95%CI: 1.051-4.992, P = 0.037), and patients with Gli1 and MDM2 co-expression had a significantly poorer overall survival than patients with their negative expression (P = 0.034). Gli1 mRNA expression was much higher in 14 cases of PDAC than that in adjacent normal pancreatic tissues (t = 2.926, P = 0.012). In p53 mutant AsPC-1 cells, Gli1 knockdown down regulated MDM2, but had no effect on p53 expression, whereas Gli1 knockdown down regulated MDM2 and up regulated p53 protein levels in p53 wild-type Capan-2 cells.
Gli1, MDM2 and p53 are overexpressed in PDAC, and are benefit for predicting patients' prognosis. Gli1can regulate MDM2 and wild-type p53 expression. Their co-expression might coordinately contribute to the development and progression of PDAC.
研究Gli1、MDM2和p53在人胰腺癌中的临床病理意义及相互关系。
采用免疫组织化学法检测57例配对的石蜡包埋胰腺导管腺癌（PDAC）标本及癌旁非癌胰腺组织中Gli1、MDM2和p53蛋白的表达，分析其表达与临床病理特征的关系。运用定量实时聚合酶链反应（qRT-PCR）检测14例配对的新鲜PDAC标本及癌旁非癌胰腺组织中Gli1 mRNA水平。采用小干扰RNA（siRNA）干扰进一步检测它们之间的密切关系。
免疫组织化学结果显示，57例胰腺癌中Gli1（50.9%）、MDM2（57.9%）和p53（56.1%）的表达高于配对的正常胰腺组织（分别为33.3%、26.3%和17.5%，t = 2.413、2.848和2.960，均P < 0.05）。Gli1表达与肿瘤TNM分期（χ(2) = 8.211，P = 0.004）、浸润深度（χ(2) = 4.247，P = 0.039）及MDM2表达（r = 0.299，χ(2) = 5.105，P = 0.024）呈正相关，而MDM2和p53表达分别与肿瘤浸润深度（χ(2) = 5.182，P = 0.023）及TNM分期（χ(2) = 5.696，P = 0.017）相关。单因素和多因素分析显示，Gli1是PDAC患者独立的不良预后指标（风险比（RR）= 2.290，95%置信区间（CI）：1.051 - 4.992，P = 0.037），Gli1与MDM2共表达患者的总生存期显著低于二者阴性表达患者（P = 0.034）。14例PDAC中Gli1 mRNA表达显著高于癌旁正常胰腺组织（t = 2.926，P = 0.012）。在p53突变的AsPC-1细胞中，敲低Gli1可下调MDM2，但对p53表达无影响；而在p53野生型Capan-2细胞中，敲低Gli1可下调MDM2并上调p53蛋白水平。
Gli1、MDM2和p53在PDAC中均呈过表达，有助于预测患者预后。Gli1可调节MDM2及野生型p53的表达，它们的共表达可能协同促进PDAC的发生发展。
