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Sen. Hepatoma Res 2018;4:37 I http://dx.doi.org/10.20517/2394-5079.2018.39 Page 5 of 7

ing factor in the fetal to adult transition in hepatocytes. Consistent with these findings, knockdown of
pre-mRNA splicing regulator SLU7 in human liver cells and mouse liver resulted in profound changes in
pre-mRNA splicing of genes essential for hepatocellular differentiation and reversion to a fetal-like gene
[40]
expression pattern . Moreover, Slu7 expression has been found to be significantly compromised in chronic
[27]
liver diseases and in HCC suggesting a role of SLU7 down-regulation in the progression of liver pathogen-
esis. Interestingly, SLU7 also preserves survival of HCC cells and other solid tumors via oncogenic miR-17-
[41]
92 cluster expression indicating a complex regulatory role of this splicing factor in pathogenesis of liver
diseases.

Hepatocyte-specific deletion of SRSF3 caused impaired hepatocyte maturation and also glucose and lipid
[42]
metabolism in early adult life . Loss of SRSF3 facilitates expression of the mitogenic isoform of insulin
receptor (IR-A) that is generally not expressed in adult liver allowing aberrant activation of mitogenic sig-
naling. Loss of SRSF3 in hepatocytes also promotes aberrant splicing and expression of EMT genes and
activates Wnt/beta-catenin signaling leading to c-Myc induction. Additionally, loss of SRSF3 promotes inclu-
sion of the profibrogenic EDA exon in fibronectin gene (FN1) and expression of the short isoform of XBP1
[36]
(XBP1s) in hepatocytes and SRSF3 knock-out mice developed spontaneous HCC with aging . In support of
[40]
this, SRSF3 has also been found to be reduced or mislocalized in human HCC , suggesting a potential pre-
ventive role of SRSF3 in HCC. Interestingly, a recent report suggests XBP1s as a newly discovered molecule
[43]
involved in the HCC progression by promoting EMT by enhancing the expression of Twist and Snail.
Pathological analysis showed that the expression of XBP1s was closely correlated with distant metastasis.

[44]
Recently, Yuan et al. identified an important oncofetal protein, MBNL3, and an oncofetal splicing event,
inclusion or skipping of lncRNA-PXN-AS1 exon 4, both of which play vital roles in hepatocarcinogenesis
and serve as prognostic biomarkers and therapeutic targets for HCC. This suggests that identifying the com-
mon molecular events between embryonic liver development and HCC would promote the understanding of
molecular pathogenesis of HCC and the development of more effective targeted therapies.

SUMMARY AND PERSPECTIVES
The findings reviewed here, though handful, are sufficient to show that the AS plays a very critical role in
regulating HCC progression and diagnostic. Thus, understanding the mechanisms of alternative pre-mRNA
splicing for HCC related genes are important for the development of new therapeutic strategies such as tar-
geting HCC specific isoform as biomarkers and targeting oncogenic isoform.

With the fast development of technologies, next generation sequencing provides a powerful way to study
the transcriptome to uncover the aberrant splicing events in different cancers including HCC. For example,
[45]
analyzing the ultra-deep transcriptome landscape of human liver cancer, Lin et al. identified potential bio-
markers for HCC, including ALG1L, SERPINA11, TMEM82 and DUNQU1 and the AS event of FGFR2. Using
antisense oligonucleotides or splicing switch oligonucleotides that can complimentarily bind to a target site
in pre-mRNAs and regulate the splicing could be used to selectively target specific isoforms of RNA with
oncogenic potential [46,47] . Targeting specific isoforms of RNA and protein has the potential to improve drug
efficacy and reduce side effects. In summary, we are hoping that the integration of pre-mRNA alternative
splicing in the pathogenesis of HCC will contribute to the better understanding of the disease and develop-
ment of new therapies.

DECLARATIONS
Authors’ contributions
The author contributed solely to the review.