Abstract
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.
Highlights
Treatment options for hepatocellular carcinoma (HCC) are limited, and overall survival is poor
Principal component analysis (PCA) (Fig. 1a) and hierarchical clustering analysis (HCA) (Fig. 1b) based on the gene expression of 458 probes divided all samples into two main groups of 13 HCC samples and another group of 10 HCC and 17 NT samples
We demonstrated that molecular tumour typing based on gene expression profiling correlated to histological grade and chromosomal instability—defining two main types of HCC—and may be used for detection of molecular markers to improve HCC therapy options
Summary
Treatment options for hepatocellular carcinoma (HCC) are limited, and overall survival is poor. Cancer tissues with different histological grades can be frequently found in individual HCC nodules [5], a phenomenon that provides a ‘nodule-in-nodule appearance’. It may be assumed by these histological findings that there is a stepwise development from low- to high-grade HCC based on molecular mechanisms that are still unknown. Chromosomal instability predicts drug resistance and poor prognosis in multiple cancer types, but the causes of chromosomal instability in HCC and other tumour types are still poorly understood [7, 8]. HCC may be divided into two main groups: one with upregulation of genes responsible for cell proliferation and anti-apoptosis and poor outcome, and the other with the opposite findings [9, 10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
