Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics

Abstract

Hepatocellular carcinoma (HCC) occurs in the chronic liver inflammation such as viral hepatitis, alcoholic and non-alcoholic steatohepatitis. While anti-viral treatment has been significantly improved, the prevalence of HCC remains high and treatment is still challenging. The continuation of hepatocyte death, inflammation, and fibrosis leads to the accumulation of gene alterations, which may trigger carcinogenesis. Hepatocytes are a unique cell type having more than one complete set of 23 chromosomes, termed polyploidy. Due to gene redundancy, hepatocytes may tolerate lethal mutations. Next generation sequencing technology has revealed gene alterations in HCC related to telomere maintenance, Wnt/β-catenin pathway, p53 cell-cycle pathway, epigenetic modifiers, oxidative stress pathway, PI3K/AKT/mTOR, and RAS/RAF/MAPK pathway with or without a chromosomal instability. Some type of driver gene mutations accumulates in hepatocytes and breaks the orchestration of excessive copies of chromosomes, which may lead to unfavorable gene expressions and fuel tumorigenesis. Recently, molecular targeted drugs, developed with the aim of interfering with these signaling pathways, are being used for HCC patients in the clinics. Therefore, a deeper understanding of hepatocyte ploidy and genetic or epigenetic alterations is indispensable for the establishment of novel therapeutic strategies against HCC.

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

“…Chronic liver disease with fibroinflammation contributes not only to fibrosis but also hepatocyte regeneration as well as replication-induced DNA damage, all of which may promote the development of liver cancer. [134][135][136][137][138][139] Extensive data have described exosomes as carriers of various cargoes conveying cellular information that enables them to serve as important players in malignant cell-nonmalignant cell communication during cancer developemnt. 88,[140][141][142] miRNA expression profiling of HSCs cocultured with liver cancer cells showed that miR-148a-3p was significantly reduced in HSCs.…”

When Mechanical Stress Matters: Generation of Polyploid Giant Cancer Cells in Tumor-like Microcapsules

“…ANXA6, S100A10, AURKA, AURKB, LGALS1), [64][65][66][67] cell proliferation and exertion of biomechanical forces (i.e. MKI67, KRT19, VIM, CDC25C), [68][69][70][71] as well as nuclei reorganization (i.e. H2AC8, H4C6, H2BC9, H2BC13, H3C7, H2AC16), [72,73] suggesting that the 3D polymer-based scaffolds may restrict -but not hinder-their proliferation, facilitating the cell-cell fusion and/or interfering with the cellular cytokinesis, enabling the generation of PGCC.…”

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

“…Both single-and double-stranded breaks (SSB and DSB) are a common feature of cell karyotype studies after cannabis exposure [7][8][9][10]12,13,99]. It therefore becomes important in the present context to note that the epigenome plays an often determinative role in influencing or selecting the site of DNA breakage generally [118][119][120][121][122][123][124][125][126][127][128][129][130][131], during meiotic crossing over [132][133][134][135][136][137][138][139], in the immune gene hypervariable region [140][141][142][143][144][145][146], and in oncogenic pathways [120,123,124,[147][148][149][150][151][152][153]…”

“…This tumor almost invariably involves the development of an isochromosome 12p. Its presence is explained by the concept of presumptive pericentromeric chromatin dysregulation as the dysregulated pericentromeric epigenome presumably facilitates the aberrant scission of the chromosome at the centromere, forming the isochromosome through the interactions between the epigenome and the genome as described above [118][119][120][121][122][123][124][125][126][127][128][129][130][131]. The presence of KIT and KRAS (and to a lesser extent NRAS) on chromosome 12 then confers a growth advantage on the mutant clone, and malignant tumorigenesis is the end result of this process continued in the context of the gross re-sculpting of the chromosomal landscape by repeated cycles of the breakage-fusion-bridge cycle across multiple cell divisions that accumulate over time.…”