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

Figure 2. Mechanisms by which SND1 promotes oncogenesis. Downstream molecules that are upregulated, downregulated or degraded
due to over expression of SND1 causing a variety of functions to go into disarray leading to tumorigenesis. Each color represents the
specific cancer in which the mechanism has been studied. In prostate cancer regulation of spliceosome assembly by SND1 results in
the production of an oncogenic variant of CD44 that promotes proliferation, motility and invasion. Tumor suppressor mRNAs that are
targets of oncogenic miRNAs are degraded when SND1 over expression confers increased RISC activity in human HCC cells. SND1
increases AT1R mRNA stability, causing an increase in AT1R levels resulting in activation of ERK and TGFβ signaling pathway, promoting
EMT and migration and invasion by human HCC cells. SND1 mediates endonucleolytic decay of tumor suppressor miRNAs in HEK293T
cells promoting upregulation of oncogenic proteins. In breast cancer cells, SND1 promotes expression of the E3 ubiquitin ligase Smurf1,
leading to RhoA ubiquitination and degradation, disrupting F-actin cytoskeletal organization, increasing cell migration and invasion, and
promoting metastasis. SND1: staphylococcal nuclease and tudor domain containing 1; HCC: hepatocellular carcinoma

SND1 AS AN ONCOGENE FOR HCC
In vitro and in vivo studies show that SND1 is an oncogene for HCC. Immunohistochemistry in tissue
microarrays containing HCC and adjacent normal liver samples revealed that SND1 is over-expressed in a
[38]
large percentage (~74%) of HCC patients . Chronic inflammation is a critical event in HCC pathogenesis
and induction by inflammatory cytokines might underlie the overexpression of SND1 in human HCC
patients. Overexpression and knockdown studies in human HCC cells have demonstrated that SND1
promotes proliferation, migration, invasion and in vivo tumorigenesis [38-41] . As a component of the RISC
[38]
in HCC cells, SND1 promotes oncogenic miRNA-mediated degradation of tumor suppressor mRNAs
[Figure 2]. Some of the mRNAs degraded are PTEN, p57, p21, SPRY2 and TGFBR2 that are targets of
[38]
miR-221 and miR-21, miR-221, miR-106b, miR-21 and miR-93, respectively . These miRNAs are known
to be overexpressed in HCC and function as oncogenes. It should be noted that the primary nuclease
in the RISC is the argonaute proteins and although a specific small molecule inhibitor of SND1 could
[23]
partially block RISC activity, SND1 may not be the primary endonuclease in the RISC . However, when
overexpressed, SND1 could significantly augment RISC activity in human HCC cells when compared to
normal hepatocytes .
[38]
By binding to and stabilizing angiotensin II type 1 receptor (AT1R) mRNA, SND1 activates TGFb and ERK
signaling, thereby promoting epithelial-mesenchymal transition (EMT), in vitro migration and invasion
[39]
by HCC cells . In HCC cells, SND1 activates NF-κB, resulting in induction of miR-221 and angiogenic
[40]
factors angiogenin and CXCL16 that promote tumor angiogenesis . Monoglyceride lipase (MGLL) inhibits
Akt activation and SND1 interacts with and induces degradation of MGLL, resulting in activation of Akt
[41]
and subsequent augmentation of cell proliferation and cell cycle progression by human HCC cells . SND1
downregulates IGFBP3 expression in human HCC cells that might result in activation of insulin-like growth
[42]
factor (IGF) signaling, a frequent event in human hepatocarcinogenesis .