Fan-En Kong1,2, Yun-Qiang Tang1, Yuan-Feng Gong1, Jia-Qiang Mo3, Yue Zhao4, Mei-Mei Li1,2, Wei Cheng1,2, Hao-Long Li1,2, Wen-Jie Zhu1,2, Shan-Shan Liu1,2, Li Huang1,2, Xin-Yuan Guan1,5, Ning-Fang Ma6,7, Ming Liu8,9. 1. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China. 2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China. 3. Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China. 4. General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany. 5. Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong. 6. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China. ningfma@163.com. 7. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China. ningfma@163.com. 8. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China. liuming@gzhmu.edu.cn. 9. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China. liuming@gzhmu.edu.cn.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: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. RESULTS: 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. CONCLUSIONS: 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.