转录共激活因子 p300 的高表达与肝癌的侵袭性特征和不良预后相关。
High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma.
机构信息
State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, PR China.
出版信息
J Transl Med. 2011 Jan 5;9:5. doi: 10.1186/1479-5876-9-5.
BACKGROUND
It has been suggested that p300 participates in the regulation of a wide range of cell biological processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear.
METHODS
In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.
RESULTS
Up-regulated expression of p300 mRNA and protein was observed in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were positively stained. High expression of p300 was examined in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival analysis, a significant association between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate analysis (P = 0.021). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001).
CONCLUSIONS
Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examined by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathologic prognostic model may become a useful tool for identifying HCC patients with different clinical outcomes.
背景
已有研究表明 p300 参与了广泛的细胞生物学过程的调控，并且在某些类型的人类癌症中已发现 p300 发生了突变。然而，p300 在肝细胞癌（HCC）中的表达动态及其临床/预后意义尚不清楚。
方法
本研究采用逆转录-聚合酶链反应（RT-PCR）、Western blot 和免疫组织化学（IHC）等方法检测 HCC 中 p300 的蛋白/信使 RNA（mRNA）表达。采用受试者工作特征（ROC）曲线分析、Spearman 秩相关、Kaplan-Meier 图和 Cox 比例风险回归模型进行数据分析。
结果
通过 RT-PCR 和 Western blot 检测，p300 的 mRNA 和蛋白在大多数 HCC 中呈现高表达，与邻近的非恶性肝组织相比。根据 ROC 曲线，当超过 60%的肿瘤细胞呈阳性染色时，将 p300 高表达的截断值定义为分数。在 123 例 HCC 中，有 60/123（48.8%）例 p300 高表达，而在 123 例邻近的非恶性肝组织中，有 8/123（6.5%）例 p300 高表达。p300 高表达与较高的 AFP 水平、较大的肿瘤大小、多发性、较差的分化程度和较晚的分期相关（P < 0.05）。在单因素生存分析中，发现 p300 过表达与患者生存时间缩短显著相关（P = 0.001）。在不同亚组的 HCC 患者中，p300 表达在 II 期（P = 0.007）和 III 期（P = 0.011）患者中也是一个预后指标。重要的是，在多因素分析中，p300 表达被评估为独立的预后因素（P = 0.021）。因此，构建了一个包含三个不良预后因素（p300 表达、AFP 水平和血管侵犯）的新的临床病理预后模型。该模型能够显著分层总生存期的风险（低、中、高）（P < 0.0001）。
结论
本研究结果为 p300 在 HCC 中高表达可能与获得侵袭性表型有关的观点提供了依据，表明通过 IHC 检测到的 p300 过表达是 HCC 患者预后不良的独立生物标志物。联合临床病理预后模型可能成为识别具有不同临床结局的 HCC 患者的有用工具。
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