Gene networks and transcriptional regulators associated with liver cancer development and progression

BMC Medical Genomics

Tatiana Meier¹  Max Timm²  Ludwig Wilkens³  Matteo Montani⁴ 

[1] Institute of Pathology, Nordstadtkrankenhaus, Hanover, Germany;Institute of Pathology, Nordstadtkrankenhaus, Hanover, Germany;Clinic for Laryngology, Rhinology and Otology, Medical School Hanover, Hanover, Germany;Institute of Pathology, Nordstadtkrankenhaus, Hanover, Germany;Institute of Human Genetics, Medical School Hanover, Hanover, Germany;Institute of Pathology, University of Bern, Bern, Switzerland;

关键词: HCC;    Chromosomal instability;    Dedifferentiation;    Gene expression;    Transcription factors;    Genomics;    Transcriptomics;   

DOI  :  10.1186/s12920-021-00883-5

来源: Springer

【 摘 要 】

BackgroundTreatment options for hepatocellular carcinoma (HCC) are limited, and overall survival is poor. Despite the high frequency of this malignoma, its basic disease mechanisms are poorly understood. Therefore, the aim of this study was to use different methodological approaches and combine the results to improve our knowledge on the development and progression of HCC.MethodsTwenty-three HCC samples were characterized by histological, morphometric and cytogenetic analyses, as well as comparative genomic hybridization (aCGH) and genome-wide gene expression followed by a bioinformatic search for potential transcriptional regulators and master regulatory molecules of gene networks.ResultsHistological evaluation revealed low, intermediate and high-grade HCCs, and gene expression analysis split them into two main sets: GE1-HCC and GE2-HCC, with a low and high proliferation gene expression signature, respectively. Array-based comparative genomic hybridization demonstrated a high level of chromosomal instability, with recurrent chromosomal gains of 1q, 6p, 7q, 8q, 11q, 17q, 19p/q and 20q in both HCC groups and losses of 1p, 4q, 6q, 13q and 18q characteristic for GE2-HCC. Gene expression and bioinformatics analyses revealed that different genes and gene regulatory networks underlie the distinct biological features observed in GE1-HCC and GE2-HCC. Besides previously reported dysregulated genes, the current study identified new candidate genes with a putative role in liver cancer, e.g. C1orf35, PAFAH1B3, ZNF219 and others.ConclusionAnalysis of our findings, in accordance with the available published data, argues in favour of the notion that the activated E2F1 signalling pathway, which can be responsible for both inappropriate cell proliferation and initial chromosomal instability, plays a pivotal role in HCC development and progression. A dedifferentiation switch that manifests in exaggerated gene expression changes might be due to turning on transcriptional co-regulators with broad impact on gene expression, e.g. POU2F1 (OCT1) and NFY, as a response to accumulating cell stress during malignant development. Our findings point towards the necessity of different approaches for the treatment of HCC forms with low and high proliferation signatures and provide new candidates for developing appropriate HCC therapies.

【 授权许可】

CC BY