核输入蛋白α1 作为肝细胞癌的一个新的预后靶点。

Importin-α1 as a novel prognostic target for hepatocellular carcinoma.

机构信息

Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.

出版信息

Ann Surg Oncol. 2011 Jul;18(7):2093-103. doi: 10.1245/s10434-011-1569-7. Epub 2011 Feb 1.

DOI:10.1245/s10434-011-1569-7

PMID:21286940

Abstract

BACKGROUND

Perturbations in the nuclear microenvironment, including transport systems, play a critical role in malignant progression, but the nuclear import abnormalities remain unclear in hepatocarcinogenesis. We analyzed the role of importin in hepatocellular carcinoma (HCC).

METHODS

Gene expression profiling of the importin family was performed in HCC tissues. The significance of importin protein expression was analyzed in vitro as well as clinicopathologically.

RESULTS

According to the microarray profiles, the importin-α1 was dominantly overexpressed in HCC tissues as compared to the adjacent noncancerous tissues. By means of human HCC cell lines, a knockdown of importin-α1 by its siRNA greatly reduced cellular proliferation by 15.2-26.6% (P < 0.005). Immunohistochemical analysis on tissue samples demonstrated cancer-specific overexpression in 36.3% of HCCs. The overexpression of importin-α1 was correlated statistically with high levels of alfa-fetoprotein ( P = 0.0017), the tumor number (P = 0.0116), histological dedifferentiation (P = 0.0054), tumor morphology (P = 0.0433), portal vein invasion (P = 0.0007), hepatic vein invasion (P = 0.0081), Fc (P = 0.0367), Fc-inf (P = 0.0122), and the tumor, node, metastasis stage (P = 0.0026); this resulted in a significantly poorer prognosis in both overall survival (P = 0.0164) and recurrence-free survival (P = 0.0101). Multivariate analysis of recurrence-free survival revealed importin-α1 expression to be a statistically significant factor (P = 0.0361). In addition, early recurrence after curative resection was observed more frequently in the importin-α1-positive group as compared to the negative group (P = 0.0023). The multivariate analysis identified importin-α1 as the only independent predictor of early recurrence after HCC resection (odds ratio = 5.291, P = 0.0191).

CONCLUSIONS

Because importin-α1 might be closely associated with HCC progression, further analysis should be pursued to evaluate it as a novel prognostic target.

摘要

背景

核微环境的改变，包括运输系统，在恶性进展中起着至关重要的作用，但在肝癌发生中核输入异常仍不清楚。我们分析了输入蛋白在肝细胞癌（HCC）中的作用。

方法

对 HCC 组织中的输入蛋白家族进行基因表达谱分析。在体外及临床病理方面分析输入蛋白的表达意义。

结果

根据微阵列图谱，与相邻的非癌组织相比，HCC 组织中输入蛋白-α1 明显过表达。通过人 HCC 细胞系，用其 siRNA 敲低输入蛋白-α1 可使细胞增殖减少 15.2-26.6%（P < 0.005）。组织样本的免疫组织化学分析显示 36.3%的 HCC 存在癌特异性过表达。输入蛋白-α1 的过表达与高水平的甲胎蛋白（P = 0.0017）、肿瘤数量（P = 0.0116）、组织学去分化（P = 0.0054）、肿瘤形态（P = 0.0433）、门静脉侵犯（P = 0.0007）、肝静脉侵犯（P = 0.0081）、Fc（P = 0.0367）、Fc-inf（P = 0.0122）和肿瘤、淋巴结、转移分期（P = 0.0026）相关；这导致总体生存率（P = 0.0164）和无复发生存率（P = 0.0101）均显著下降。无复发生存率的多变量分析显示输入蛋白-α1 表达是一个统计学上显著的因素（P = 0.0361）。此外，与阴性组相比，根治性切除术后早期复发更常见于输入蛋白-α1 阳性组（P = 0.0023）。多变量分析确定输入蛋白-α1 是 HCC 切除术后早期复发的唯一独立预测因子（优势比=5.291，P = 0.0191）。