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

Some tumor suppressors are also self-inactivated in HCC by alternative splicing. The tumor suppressor
isoform of TP73 gene is TAp73, which promotes apoptosis and limits the anchorage-independent growth of
tumor cells. Truncated isoforms (ΔEx2p73, ΔEx2/3p73, and ΔN’p73) of TP73 are generated by aberrant splic-
[27]
ing and serve as dominant negative inhibitors of TAp73 and inhibit its tumor suppressor activity . Several
studies have shown that these isoforms are over-expressed in HCC compared to normal liver and correlated
[28]
with poor patient prognosis . In HCC, ΔEx2p73 expression is correlated with activation of the epidermal
growth factor receptor (EGFR) and the down-regulation of the mRNA splicing factor Slu7. From a mecha-
nistic perspective, activation of EGFR by its ligand amphiregulin (AR), whose expression is up-regulated in
[27]
HCC, and c-Jun N-terminal kinase-1 activity facilitates TAp73 alternative splicing and ΔEx2p73 production .

Tumor suppressor KLF6 that regulates many genes involved in cell cycle, apoptosis and differentiation also
[29]
inactivated by its dominant-negative SV1 isoform in HCC . Studies found that SV1 isoform of KLF6 is
over-expressed in HCC that promotes cellular proliferation and KLF6 full form is decreased in HCC tissue.
The oncogenic activation of the Ras/PI3K/Akt pathway and subsequent down regulation of splice regulatory
protein ASF/SF2 or SRSF1 leads to this aberrant splicing of KLF6 in HCC. Also, upstream of Ras, the EGFR
[29]
tyrosine kinase activity could potentially trigger KLF6 SV1 generation . These findings suggest potential
antagonistic functions of the two isoforms in HCC and relative abundance of the isoforms might dictate the
cellular fate. Thus, unraveling the regulatory mechanisms that promote these aberrant splicing might pro-
vide effective molecular targets for HCC therapy.

ABERRANT REGULATION OF SPLICING FACTORS AND ONCOFETAL TRANSFORMATION IN

HCC
Aberrant expression or activity of splicing factors is a major cause of splicing deregulation; thus, it is quite
expected that, increased or decreased expression of crucial splicing factors leads to disease. Indeed, deregu-
lation of splicing regulators such as SRSF1, SRSF10, RBFOX2, MBNL1/2, and QKI proteins has been ob-
served and accounts for hundreds of altered alternative splicing events present in multiple cancer types [30-32] .
In HCC, the splicing dysregulation may be influenced by down-regulation of splicing factors ESRP2,
CELF2 and SRSF5 and up-regulation of splicing factors SRSF1 or SF2/ASF, SRSF2, hnRNPA1, hnRNPA2B1,
hnRNPH and CUGBP1. In multiple HCC samples, decreased expression of ESRP2, CELF2 and SRSF5 were
[17]
observed , whereas, a significant correlation was found between the increased expression of IR-A and up-
[20]
regulation of splicing factors SRSF1, hnRNPA1, hnRNPA2B1, hnRNPH, and CUGBP1 . This observation is
in agreement with the previous in vitro studies that showed, SRSF1, CUGBP1 and hnRNPA1 promote IR-A
expression in hepatoma cell-lines [33,34] . Studies showed that overexpression of the SR proteins SRSF1 and
[35]
SRSF3 promote tumor growth in nude mice and these proteins are elevated in certain cancers . Interest-
[36]
ingly, in the mouse model, hepatocyte-specific deletion of SRSF3 caused spontaneous HCC with aging ,
suggesting that the function of individual splicing factor depends on the cellular context. It was observed
that the splicing factors that play important roles in the maturation of liver, down-regulation of those factors
promoting HCC. Studies have shown that embryonic liver development and HCC share similar alterations
in many genetic programs, and HCC patients with gene expression profiles similar to embryonic stem cells
had a worse prognosis [37,38] . Also, in case of HCC, it has been observed that different mRNA isoforms that are
developmentally regulated and not generally expressed in the adult liver, are often expressed in cancer tissue.
However, little is known about the mechanisms driving hepatocellular dedifferentiation during chronic liver
diseases and tumor development.

Expression of splicing factor Esrp2 is increased in the adult liver as this splicing factor plays an important
role in mesenchymal to epithelial transformation (MET) that is the opposite of epithelial to mesenchymal
[39]
transformation (EMT), observed in cancer tissues. Studies showed that, homozygous knockout of Esrp2
led to impaired adult splicing patterns in the liver in the mouse model, suggesting the role of this splic-