Coulouarn Cédric, Factor Valentina M, Thorgeirsson Snorri S
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hepatology. 2008 Jun;47(6):2059-67. doi: 10.1002/hep.22283.
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The clinical heterogeneity of HCC, and the lack of good diagnostic markers and treatment strategies, has rendered the disease a major challenge. Patients with HCC have a highly variable clinical course, indicating that HCC comprises several biologically distinctive subgroups reflecting a molecular heterogeneity of the tumors. Transforming growth factor beta (TGF-beta) is known to exhibit tumor stage dependent suppressive (that is, growth inhibition) and oncogenic (that is, invasiveness) properties. Here, we asked if a TGF-beta specific gene expression signature could refine the classification and prognostic predictions for HCC patients. Applying a comparative functional genomics approach we demonstrated that a temporal TGF-beta gene expression signature established in mouse primary hepatocytes successfully discriminated distinct subgroups of HCC. The TGF-beta positive cluster included two novel homogeneous groups of HCC associated with early and late TGF-beta signatures. Kaplan-Meier plots and log-rank statistics indicated that the patients with a late TGF-beta signature showed significantly (P < 0.005) shortened mean survival time (16.2 +/- 5.3 months) compared to the patients with an early (60.7 +/- 16.1 months) TGF-beta signature. Also, tumors expressing late TGF-beta-responsive genes displayed invasive phenotype and increased tumor recurrence. We also showed that the late TGF-beta signature accurately predicted liver metastasis and discriminated HCC cell lines by degree of invasiveness. Finally, we established that the TGF-beta gene expression signature possessed a predictive value for tumors other than HCC.
These data demonstrate the clinical significance of the genes embedded in TGF-beta expression signature for the molecular classification of HCC.
肝细胞癌（HCC）是世界上最常见的癌症之一。HCC的临床异质性以及缺乏良好的诊断标志物和治疗策略，使其成为一个重大挑战。HCC患者的临床病程高度可变，这表明HCC包含几个生物学上不同的亚组，反映了肿瘤的分子异质性。已知转化生长因子β（TGF-β）具有肿瘤阶段依赖性抑制（即生长抑制）和致癌（即侵袭性）特性。在此，我们询问TGF-β特异性基因表达特征是否可以优化HCC患者的分类和预后预测。应用比较功能基因组学方法，我们证明在小鼠原代肝细胞中建立的时间性TGF-β基因表达特征成功区分了HCC的不同亚组。TGF-β阳性簇包括与早期和晚期TGF-β特征相关的两个新的HCC同质组。Kaplan-Meier图和对数秩统计表明，与具有早期TGF-β特征（60.7±16.1个月）的患者相比，具有晚期TGF-β特征的患者平均生存时间显著缩短（P<0.005）（16.2±5.3个月）。此外，表达晚期TGF-β反应基因的肿瘤表现出侵袭性表型并增加肿瘤复发。我们还表明，晚期TGF-β特征准确预测肝转移并按侵袭程度区分HCC细胞系。最后，我们确定TGF-β基因表达特征对HCC以外的肿瘤具有预测价值。
这些数据证明了TGF-β表达特征中所包含基因对HCC分子分类的临床意义。
