title: Transcriptomic analysis of a transgenic zebrafish hepatocellular carcinoma model reveals a prominent role of immune responses in tumour progression and regression.
abstract: Using our previously established xmrk transgenic zebrafish, hepatocellular carcinoma (HCC) was generated by induced expression of xmrk, which encoded a hyperactive epidermal growth factor receptor (EGFR) homolog, and regressed by suppression of xmrk expression. To investigate molecular changes in liver tumour progression and regression, RNA-Seq was performed for induced HCC and early and late stages of liver tissues during tumour regression. We found that Xmrk-induced zebrafish HCC shared strong molecular characteristics with a human HCC subtype (S2), which shows activated Myc signalling, upregulated phosphor-S6 and epithelial cell adhesion molecule. In the HCC stage, there were enhanced proteasome, antigen processing and presentation, aminosugars metabolisms, p53 and cell cycle pathways. During tumour regression, the transcriptomic profile showed a reversed trend of molecular changes compared with human HCC progression. Interestingly, distinct immune responses in tumour progression and regression were observed, including increased major histocompatibility complex class I (MHCI) at the HCC stage, enriched immune cell trafficking signals and inflammation in early regression and enhanced MHCII in late regression. Both neutrophils and macrophages were enriched during tumour progression and regression; however, the distribution of neutrophils and macrophages in HCC was relatively uniform, whereas both types of immune cells were regionally clustered during tumour regression, especially with dominant blood vessel association of macrophage in late regression, suggesting differential functions of these immune cells in tumour progression and regression. As tumour regression in our model resembles the targeted inhibition of EGFR in cancer therapy, our observations may provide molecular insights into the targeted inhibition and highlight the importance of immune response in tumour regression.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore; Human genetics 2, Genome Institute of Singapore, Singapore.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Huaien
authors.initials: H
authors.lastname: Luo
authors.forename: Caixia
authors.initials: C
authors.lastname: Li
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huo
authors.forename: Chuan
authors.initials: C
authors.lastname: Yan
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Huang
authors.forename: Muthafar
authors.initials: M
authors.lastname: Al-Haddawi
authors.forename: Sinnakaruppan
authors.initials: S
authors.lastname: Mathavan
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Gong
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016612:Paraffin Embedding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: RNA-Seq; epidermal growth factor receptor; hepatocellular carcinoma; immune response; tumour regression