Desoteux Matthis, Louis Corentin, Bévant Kevin, Glaise Denise, Coulouarn Cédric
Inserm, Univ. Rennes, UMR1242, Chemistry Oncogenesis Stress Signaling (COSS), 35042 Rennes, France.
Inserm, Univ. Rennes, UMR991, Liver Metabolisms and Cancer, 35043 Rennes, France.
Cancers (Basel). 2021 Nov 10;13(22):5624. doi: 10.3390/cancers13225624.
Hepatocellular carcinoma (HCC) is a deadly cancer worldwide as a result of a frequent late diagnosis which limits the therapeutic options. Tumor progression in HCC is closely correlated with the dedifferentiation of hepatocytes, the main parenchymal cells in the liver. Here, we hypothesized that the expression level of genes reflecting the differentiation status of tumor hepatocytes could be clinically relevant in defining subsets of patients with different clinical outcomes. To test this hypothesis, an integrative transcriptomics approach was used to stratify a cohort of 139 HCC patients based on a gene expression signature established in vitro in the HepaRG cell line using well-controlled culture conditions recapitulating tumor hepatocyte differentiation. The HepaRG model was first validated by identifying a robust gene expression signature associated with hepatocyte differentiation and liver metabolism. In addition, the signature was able to distinguish specific developmental stages in mice. More importantly, the signature identified a subset of human HCC associated with a poor prognosis and cancer stem cell features. By using an independent HCC dataset (TCGA consortium), a minimal subset of seven differentiation-related genes was shown to predict a reduced overall survival, not only in patients with HCC but also in other types of cancers (e.g., kidney, pancreas, skin). In conclusion, the study identified a minimal subset of seven genes reflecting the differentiation status of tumor hepatocytes and clinically relevant for predicting the prognosis of HCC patients.
肝细胞癌（HCC）是一种在全球范围内都具有致命性的癌症，因其诊断往往较晚，这限制了治疗选择。HCC中的肿瘤进展与肝细胞（肝脏中的主要实质细胞）的去分化密切相关。在此，我们假设反映肿瘤肝细胞分化状态的基因表达水平在定义具有不同临床结局的患者亚组方面可能具有临床相关性。为了验证这一假设，我们采用了一种整合转录组学方法，基于在HepaRG细胞系中利用模拟肿瘤肝细胞分化的严格控制培养条件在体外建立的基因表达特征，对139例HCC患者队列进行分层。首先通过鉴定与肝细胞分化和肝脏代谢相关的强大基因表达特征来验证HepaRG模型。此外，该特征能够区分小鼠中的特定发育阶段。更重要的是，该特征鉴定出了一部分与预后不良和癌症干细胞特征相关的人类HCC。通过使用一个独立的HCC数据集（TCGA联盟），结果显示一个由七个与分化相关的基因组成的最小子集不仅能预测HCC患者的总生存期缩短，还能预测其他类型癌症（如肾癌、胰腺癌、皮肤癌）患者的总生存期缩短。总之，该研究鉴定出了一个由七个基因组成的最小子集，其反映了肿瘤肝细胞的分化状态，并且在预测HCC患者的预后方面具有临床相关性。
