Fuliang Qian1, Jinghan Wang2, Ying Wang2, Qian Gao3, Wenying Yan1, Yuxin Lin3, Li Shen4, Yufeng Xie1,3, Xiaoqing Jiang2, Bairong Shen4. 1. Center for Systems Biology, Soochow University, Suzhou, China. 2. Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, Shanghai, China. 3. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China. 4. Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant disease with high morbidity and mortality, and the molecular mechanism for the genesis and progression is complex and heterogeneous. Biomarker discovery is crucial for the personalized and precision treatment of HCC. The accumulation of reported microRNA biomarkers makes it possible to combine computational identification with experimental validation to accelerate the discovery of novel biomarker. RESULTS: In the present work, we applied a rational computer-aided biomarker discovery model to screen for the HCC diagnosis biomarker. Two HCC-associated networks were constructed based on the microRNA and mRNA expression profiles, and the potential microRNA biomarkers were identified based on their unique regulatory and influential power in the network. These putative biomarkers were then experimentally validated. One prominent example among these identified biomarkers is MiR-378a-3p: It was shown to independently regulate several important transcription factors such as PLAGL2 and β-catenin, affecting the β-catenin signaling. Such mechanism may indicate a potential tumor suppressor role of MiR-378a-3p and the impact of its abnormal expression on the cell growth and invasion of HCC. CONCLUSIONS: A bioinformatics model with network topological and functional characterization was successfully applied to the identification of HCC biomarkers. The predicted microRNA biomarkers were than validated with experiments using human HCC cell lines, model animal, and clinical specimens. The results confirmed the prediction by our proposed model that miR-378a-3p was a putative biomarker for diagnosis and prognosis of HCC.
BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant disease with high morbidity and mortality, and the molecular mechanism for the genesis and progression is complex and heterogeneous. Biomarker discovery is crucial for the personalized and precision treatment of HCC. The accumulation of reported microRNA biomarkers makes it possible to combine computational identification with experimental validation to accelerate the discovery of novel biomarker. RESULTS: In the present work, we applied a rational computer-aided biomarker discovery model to screen for the HCC diagnosis biomarker. Two HCC-associated networks were constructed based on the microRNA and mRNA expression profiles, and the potential microRNA biomarkers were identified based on their unique regulatory and influential power in the network. These putative biomarkers were then experimentally validated. One prominent example among these identified biomarkers is MiR-378a-3p: It was shown to independently regulate several important transcription factors such as PLAGL2 and β-catenin, affecting the β-catenin signaling. Such mechanism may indicate a potential tumor suppressor role of MiR-378a-3p and the impact of its abnormal expression on the cell growth and invasion of HCC. CONCLUSIONS: A bioinformatics model with network topological and functional characterization was successfully applied to the identification of HCC biomarkers. The predicted microRNA biomarkers were than validated with experiments using human HCC cell lines, model animal, and clinical specimens. The results confirmed the prediction by our proposed model that miR-378a-3p was a putative biomarker for diagnosis and prognosis of HCC.
Keywords:
cancer genesis and progression; hepatocellular carcinoma (HCC); microRNA biomarker; network structure characterization; unique regulatory and influential power
Authors: Azra Krek; Dominic Grün; Matthew N Poy; Rachel Wolf; Lauren Rosenberg; Eric J Epstein; Philip MacMenamin; Isabelle da Piedade; Kristin C Gunsalus; Markus Stoffel; Nikolaus Rajewsky Journal: Nat Genet Date: 2005-04-03 Impact factor: 38.330