Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China.
Hepatol Int. 2020 Jul;14(4):521-533. doi: 10.1007/s12072-020-10035-z. Epub 2020 Apr 17.
Loss of terminal differentiation markers and gain of stem cell-like properties are a major hallmark of cancer malignant progression. Identification of novel biomarkers representing tumor developmental progeny and predictive of patients' prognosis would greatly benefit clinical cancer management.
Human embryonic stem cells were induced to differentiate into hepatocytes along hepatic lineages. Transcriptomic data from different liver developmental stages were analyzed combining with the RNA-seq data from The Cancer Genome Atlas (TCGA) project. Kaplan-Meier survival analysis and Cox regression analyses were used to analyze the clinical significance in HCC patients.
A shifted expression pattern of claudin (CLDN) family genes were identified to be closely associated with liver development and tumor progression. Claudins with hepatic features were found to be significantly down-regulated and predicted better prognosis in HCC patients. Conversely, another set of claudins with embryonic stem cell features were found to be significantly up-regulated and predicted worse prognosis in HCC patients. A claudin signature score system was further established by combining the two sets of claudin genes. The newly established claudins signature could robustly predict HCC patients' prognosis in the training, testing, and independent validation cohorts.
In the present study, we developed a novel embryonic developmental claudins signature to monitor the extent of tumor dedifferentiation in HCC from an in vitro hepatocyte differentiation model. The claudins signature might present a great potential in predicting prognostic significance in HCC as cell surface biomarkers, and provide novel therapeutic targets for precision oncology further in the clinic.
失去终末分化标志物和获得干细胞样特性是癌症恶性进展的主要标志。鉴定代表肿瘤发育后代的新型生物标志物，并预测患者的预后，将极大地有益于临床癌症管理。
人胚胎干细胞被诱导沿着肝谱系分化为肝细胞。结合癌症基因组图谱（TCGA）项目的 RNA-seq 数据，分析来自不同肝发育阶段的转录组数据。采用 Kaplan-Meier 生存分析和 Cox 回归分析方法分析 HCC 患者的临床意义。
发现紧密关联肝发育和肿瘤进展的 Claudin（CLDN）家族基因的表达模式发生偏移。具有肝特征的 Claudin 明显下调，预测 HCC 患者预后较好。相反，另一组具有胚胎干细胞特征的 Claudin 则明显上调，预测 HCC 患者预后较差。通过结合这两组 Claudin 基因，进一步建立 Claudin 特征评分系统。该 Claudin 特征评分系统在训练、测试和独立验证队列中均能稳健地预测 HCC 患者的预后。
本研究通过体外肝细胞分化模型，开发了一种新型的胚胎发育 Claudin 特征评分系统，用于监测 HCC 肿瘤去分化的程度。 Claudin 特征评分系统作为细胞表面标志物，在预测 HCC 的预后意义方面具有很大的潜力，并为临床精准肿瘤学提供了新的治疗靶点。
