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Chidambaranathan-Reghupaty et al. Hepatoma Res 2018;4:32 I http://dx.doi.org/10.20517/2394-5079.2018.34 Page 5 of 10

In vivo studies with hepatocyte specific SND1 over-expressing mice (Alb/SND1) showed that transgenic
animals have a higher incidence of spontaneous tumors, an increase in CD133+, CD44+ and EpCAM+
[43]
tumor initiating cells (TICs) and an increase in HCC drivers (c-Myc, TNFα and IL-6) . Upon treatment
with a liver carcinogen, diethylnitrosamine (DEN), Alb/SND1 mice showed robustly aggressive tumor
response and an increased expression of HCC (AFP and CD36), angiogenesis (CD31) and proliferation
(PCNA) markers. Mechanistically, SND1 overexpression activates Akt, ERK, and NF-κB signaling. Inhibitor
studies unraveled roles of Akt and NF-κB signaling in regulating SND1-induced increase in TIC while ERK
pathway was shown to regulate SND1-induced invasion [Figure 2]. A small molecule inhibitor of SND1, 3’,
5’-deoxythymidine bisphosphate (pdTp), significantly inhibited growth of orthotopic xenografts of human
HCC cells in nude mice accompanied by decrease in markers of TIC and inflammation, thereby confirming
[43]
SND1 as a potential therapeutic target for HCC and utility of pdTp as a therapeutic agent .

SND1 AND INFLAMMATION
HCC initiation and progression are multistep processes. More than 90% of HCCs arise with hepatic injury
[44]
and chronic inflammation in the background . Inflammation is also a hallmark of NASH, a growing
public health concern and a major cause of HCC [45,46] . Hepatic injury from viral infections, alcohol or high
fat diet can cause cell death and the release of molecules called damage associated molecular patterns
(DAMPs) that start the inflammatory cascade as a wound-healing response. The transcription factor
NF-κB, regulating a diverse array of pro-inflammatory cytokines, chemokines and adhesion molecules, is
the single most important molecule causing inflammation. Overexpression of SND1, either in HCC cell
lines or in Alb/SND1 mice, resulted in marked activation of NF-κB, and Alb/SND1 mice presented with
increased levels of pro-inflammatory cytokines, such as IL-6 and TNFα, thereby providing a link between
[13]
SND1 and inflammation [40,43] . On the other hand, SND1 itself is regulated by NF-κB . Thus a vicious
cycle exists where SND1 augments inflammation and the inflammatory process in turn induces SND1 that
might cause predisposition to the development of HCC. As yet, the molecular mechanism by which SND1
activates NF-κB remains to be determined. In primary hepatocytes, inhibition of SND1 activity by pdTp
not only abrogated LPS-induced nuclear translocation of p65 subunit of NF-κB but also reduced the level of
[43]
total p65 . This finding was also observed in human HCC xenografts in nude mice that were treated with
[43]
pdTp . These findings suggest that as a transcriptional coactivator SND1 might be involved in regulating
the expression of p65 itself, a hypothesis that needs to be interrogated.

SND1 AND STRESS RESPONSE
Under normal physiology, cells respond to stress by activating survival pathways to overcome stress or
cell death pathways to eliminate damaged cells. A number of factors determine how cells choose between
these two responses, and in the context of cancer a variety of proteins promote cell survival rather than cell
death to augment tumorigenesis. SND1 seems to have a role in this stress-induced pro-survival signaling.
Cells respond to conditions like oxidative stress, heat shock, viral infection, UV irradiation, DNA damage
and hyperosmotic stress by forming stress granules (SGs) that are dense aggregations of translation-stalled
mRNAs bound to messenger ribonucleoproteins (mRNPs) in the cytosol. Cancer cells use stress granules as
a means to promote survival under adverse conditions of the tumor microenvironment. SND1 was identified
[47]
as a component of cytoplasmic stress granules formed in response to oxidative stress . Ras GTPase
activating protein SH3 domain binding protein (G3BP) is a phosphorylation dependent endoribonuclease
that assembles stress granules and potentially degrades the SG mRNAs. Under oxidative stress, c-JNK
phosphorylates SND1 at threonine 103, promoting the binding of its SN domain with G3BP to form stress
[48]
granules . It is not yet clear if the role of SND1 is limited to assembling these SGs or extends beyond that
where the endonuclease activity of SND1 participates in degrading SG mRNAs.

Unfolded protein response or endoplasmic reticulum (ER) stress plays an important role in regulating
[49]
NASH and NASH-induced HCC . ER stress can be simulated in vitro by exposing cells to thapsigargin,