Science China Life Sciences

, Volume 62, Issue 11, pp 1481–1491 | Cite as

Identification of hedgehog signaling as a potential oncogenic driver in an aggressive subclass of human hepatocellular carcinoma: A reanalysis of the TCGA cohort

  • Yang Zhao
  • Li Zhang
  • Yong Zhang
  • Bo Meng
  • Wantao YingEmail author
  • Xiaohong QianEmail author
Research Paper


Hepatocellular carcinoma (HCC) is a heterogeneous disease and the second most common cause of cancer-related death worldwide. Marked developments in genomic technologies helped scientists to understand the heterogeneity of HCC and identified multiple HCC-related molecular subclasses. An integrative analysis of genomic datasets including 196 patients from The Cancer Genome Atlas (TCGA) group has recently reported a new HCC subclass, which contains three subgroups (iCluster1, iCluster2, and iCluster3). However, the transcriptional molecular characteristics underlying the iClusters have not been thoroughly investigated. Herein, we identified a more aggressive subset of HCC patients in the iCluster1, and re-clustered the TCGA samples into novel HCC subclasses referred to as aggressive (Ag), moderate-aggressive (M-Ag), and less-aggressive (L-Ag) subclasses. The Ag subclass had a greater predictive power than the TCGA iCluster1, and a higher level of alpha fetoprotein, microscopic vascular invasion, immune infiltration, isocitrate dehydrogenase 1/2 mutation status, and a worse survival than M-Ag and L-Ag subclasses. Global transcriptomic analysis showed that activation of hedgehog signaling in the Ag subclass may play key roles in tumor development of aggressive HCC. GLI1, a key transcriptional regulator of hedgehog signaling upregulated in the Ag subclass, was correlated with poor prognosis of HCC, and may be a potential prognostic biomarker and therapeutic target for Ag subclass HCC patients.


hepatocellular carcinoma The Cancer Genome Atlas molecular subclass Wnt hedgehog 



We are grateful for the financial support from the National Key Program for Basic Research of China (2017YFC0906603, 2017YFC0908404, 2016YFA0501300), the National Natural Science Foundation of China (81530021), the Beijing Municipal Science and Technology Project (Z161100002616036), and the Innovation Foundation of Medicine (BWS14J052, 16CXZ027). We thank all the researchers who contributed to the genomic characterization of HCC during the previous two decades, hence allowing this comparative analysis. We thank the TCGA groups for providing the publicly available source data.

Supplementary material

11427_2019_9560_MOESM1_ESM.xlsx (151 kb)
Table S1 Up- and down-regulation signature genes of Ag subclass


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Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Life Science and BioengineeringBeijing University of TechnologyBeijingChina
  2. 2.State Key Laboratory of Proteomics, Beijing Proteome Research CenterNational Center for Protein Sciences (Beijing), Beijing Institute of LifeomicsBeijingChina
  3. 3.Center for Bioinformatics and Computational Biology, Institute of Biomedical Sciences, School of Life SciencesEast China Normal UniversityShanghaiChina
  4. 4.School of Statistics, Faculty of Economics and ManagementEast China Normal UniversityShanghaiChina
  5. 5.Key Lab of Transplant Engineering and Immunology, West China-Washington Mitochondria and Metabolism Research Center, West China HospitalSichuan UniversityChengduChina

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