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Review
. 2018 Oct 27;10(10):645-661.
doi: 10.4254/wjh.v10.i10.645.

Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma

Olga Krivtsova  1 , Anna Makarova  1 , Natalia Lazarevich  1
Affiliations
Review

Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma

Olga Krivtsova et al. World J Hepatol. .

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.

Keywords: Alternative isoforms; Alternative splicing; Hepatic differentiation; Hepatocellular carcinoma; Personalized treatment; Transcription factors.

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Conflict of interest statement

Conflict-of-interest statement: All authors declare no potential conflicts of interest related to this manuscript.

Figures

Figure 1
Figure 1
Alternative transcription factor isoforms possess regulatory properties distinct from those of canonical variants. Schematic representation of the common isoform formation mechanisms - alternative splicing, alternative promoter usage and alternative initiation of translation - is shown in the central part of the hexagon. Light boxes correspond to constitutive exons, and dark ones designate the exons harboring domains and regions indicated in the adjacent frame. TF isoform properties divergent from those of the canonical variants and resulting from functional domain loss are indicated at the corresponding hexagon edges on the outer side of the frame. The brace marks exon exclusion - a particular case of alternative splicing. The arrows represent transcription start sites. AUG: Start codon; TR: Transcription repression; TRD: Transcription repression domain; TF: Transcription factor; TAD: Trans-activation domain; LBD: Ligand-binding domains; DBD: DNA-binding; NLS: Nuclear localization signal.
Figure 2
Figure 2
The key processes implicated in hepatocarcinogenesis that are regulated by transcription factors or their specific isoforms. TFs with stimulatory effects on these properties are depicted in green color, and TFs acting as repressors are colored in red. Sharp arrows indicate the stimulation of HCC development, and inhibition is indicated by blunt arrows. TF: Transcription factor; HCC: Hepatocellular carcinoma; EMT: Epithelial-mesenchymal transition.
See this image and copyright information in PMC

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