Abstract
Hepatocellular carcinoma develops as a multistep process, in which cell cycle deregulation is a central feature, resulting in unscheduled proliferation. The PLAGL1 gene encodes a homonym zinc finger protein that is involved in cell-proliferation control. We determined the genomic profile and the transcription and expression level of PLAGL1, simultaneously with that of its molecular partners p53, PPARγ and p21, in cell-lines derived from patients with liver cancer, during in vitro cell growth. Our investigations revealed that genomic and epigenetic changes of PLAGL1 are also present in hepatoma cell-lines. Transcription of PLAGL1 in tumor cells is significantly lower than in normal fibroblasts, but no significant differences in terms of protein expression were detected between these two cell-types, indicating that there is not a direct relationship between the gene transcriptional activity and protein expression. RT-PCR analyses on normal fibroblasts, used as control, also showed that PLAGL1 and p53 genes transcription occurs as an apparent orchestrated process during normal cells proliferation, which gets disturbed in cancer cells. Furthermore, abnormal trafficking of the PLAGL1 protein may occur in hepatocarcinogenesis.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third cause of death cancer worldwide
Considering that loss of heterozygosity (LOH) at the PLAGL1 locus and hypermethylation of its P1 promoter occur more frequently than gene mutations, the mechanisms by which this gene participates in the tumorigenic process seem to be different from those of typical tumor suppressor gene (TSG)
Punctual mutations of the PLAGL1 gene were detected in only 71 (0.3%) out of 21,029 tumor samples of all kind registered in the Catalog of Somatic Mutations in Cancer (COSMIC; http://cancer.sanger. ac.uk/cosmic)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third cause of death cancer worldwide. HCC is widely distributed around the world, presenting higher incidence in sub-Saharan Africa and Eastern Asia than Northern Europe, Oceania and America [1]. This uneven geographical distribution is closely related to that of the risk factors which vary among regions. The hepatitis B and C virus infections are common in Asia and Japan, respectively, whereas obesity and non-alcoholic liver disease lead to an increased incidence of HCC in United States and other western countries [2]. Structural and/or functional alterations of proteins that participate in these pathways, leading to cell-cycle deregulation are frequently found in HCC cells [7]. While in vitro studies, using the HepG2, SkHep and Huh cell lines derived from human heptomas demonstrated that down-regulation of the COMMD7 gene and the treatment with isocorydine and interferons favour inhibition of cell proliferation and induction of apoptosis [9,10,11]
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