Association of Autophagy Defect with a Malignant Phenotype and Poor Prognosis of Hepatocellular Carcinoma
Association of Autophagy Defect with a Malignant Phenotype and Poor Prognosis of Hepatocellular Carcinoma
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自噬缺陷与肝细胞癌恶性表型和不良预后的关系
DOI：
10.1158/0008-5472.can-08-1573
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Ding, Zhen-Bin;Shi, Ying-Hong;Fan, Jia
肝细胞癌（HCC）是一种侵袭性癌症，预后差。自噬在HCC中的作用和自噬基因的预后价值在很大程度上是未知的。在这里，我们发现自噬基因的表达和相应的自噬活性降低，抗凋亡基因的表达增加。与正常肝细胞系相比，HCC细胞系中的Bcl-xL基因。我们还发现44例肝癌组织中自噬基因Beclin I的表达与邻近的非肿瘤组织相比降低。此外，我们发现最具侵袭性的恶性HCC细胞系和复发性HCC组织显示出低得多的自噬水平，特别是当Bcl-xL过表达时。有趣的是，在一项由300名接受根治性切除术的HCC患者组成的组织微阵列研究中，Beclin 1的表达仅与Bcl-xL（+）组的无病生存期（DFS; P <0.0001）和总生存期（OS; P < 0.0001）显著相关。多因素和单因素分析也显示Beclin I表达是Bcl-xL（+）患者DFS和OS的独立预测因子。此外，我们发现Bcl-xL（+）HCC患者Beclin I表达与肿瘤分化之间存在显著相关性，而Bcl-xL（-）HCC患者则无相关性。总之，我们的数据显示自噬基因的表达和相应的自噬活性在HCC中被抑制。自噬缺陷与凋亡活性的改变协同作用可能促进肿瘤恶性分化，从而导致更具侵袭性的癌细胞表型和HCC的不良预后。[Cancer Res 2008; 68（22）：9167-75]
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The role of autophagy and the prognostic value of autophagic genes are largely unknown in HCC. Here, we showed decreased expression of autophagic genes and their corresponding autophagic activity and increased expression of the antiapoptotic. gene Bcl-xL in HCC cell lines compared with a normal hepatic cell line. We also found decreased expression of the autophagic gene Beclin I in 44 HCC tissue samples compared with adjacent nontumor tissues. In addition, we found that the most aggressive malignant HCC cell lines and HCC tissues with recurrent disease displayed much lower autophagic levels, especially when Bcl-xL was overexpressed. Interestingly, in a tissue microarray study consisting of 300 HCC patients who underwent curative resection, the expression of Beclin 1 was only significantly correlated with disease-free survival (DFS; P < 0.0001) and overall survival (OS; P < 0.0001) in the Bcl-xL(+) group. Multivariate and univariate analyses also revealed that Beclin I expression was an independent predictor for DFS and OS in Bcl-xL(+) patients. In addition, we found a significant correlation between Beclin I expression and tumor differentiation in Bcl-xL(+) but not in Bcl-xL(-) HCC patients. In conclusion, our data showed expression of autophagic genes and their corresponding autophagic activities were suppressed in HCC. The autophagy defects synergized with altered apoptotic activity might facilitate tumor malignant differentiation, which results in a more aggressive cancer cell phenotype and poor prognosis of HCC. [Cancer Res 2008; 68(22):9167-75]