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Chia et al. Hepatoma Res 2019;5:9 I http://dx.doi.org/10.20517/2394-5079.2018.112 Page 7 of 14

showed re-localization of β-catenin to cytoplasm, concomitant reduction in cyclin D1 and increase in
tumour suppressor retinoblastoma. In addition, CDH17 was reported as an useful diagnostic marker for
[95]
adenocarcinomas of the digestive system . It was also associated with bone marrow metastasis of breast
[96]
[93]
cancer and liver metastasis of colorectal cancer .
CDH17 expression was upregulated by 2.5 to 800 folds in over 80% HCC but not in healthy liver, making
+
[88]
it an attractive diagnostic and therapeutic biomarker for HCC . Half of the CDH17 HCC patients have
gained genomic copy of this gene. Importantly, alternately spliced mRNA transcripts, characterized by
loss of exon 7, were reported in roughly half of the HCC patient specimens. The splicing introduced a pre-
mature stop codon in the open-reading frame and resulted in a truncated CDH17 protein. It was speculated
that overexpression of the truncated variant may act as a dominant inhibitor of wild-type CDH17, thereby
enhancing tumour invasion. In consistent to this speculation, expression of this variant CDH17 was strongly
associated with poorer overall survival, higher risk of relapse and venous infiltration after hepatectomy.
The spliced transcripts were only detected in HCC samples but not normal liver samples, implying that the
splicing is likely to be an aberrant cancerous event rather than a normal splicing phenomenon. Importantly,
an antibody against the RGD motif of CDH17 has shown promising anti-tumour effects against metastatic
[97]
colon cancer and melanoma, suggesting that it is likely to be effective against HCC .
YAP1
YAP1, also known as YAP or YAP65, is an oncogene encoded by the YAP1 gene located on human
[98]
chromosome 11 (11q22) . It is a downstream nuclear effector of the Hippo signaling pathway, which
[99]
is important for development, cell proliferation, repair and homeostasis . Given its importance in cell
proliferation, YAP1 knockout mice showed development arrest and died prematurely [100] . Studies on the
Drosophila Yorkie (Yki) protein, an ortholog of YAP1, suggested that YAP1 is negatively regulated by the
Hippo pathway [101] . Inactivation of Hippo pathways leads to accumulation of Yki proteins in the nucleus
and upregulation of genes associated with cell survival and proliferation, including cycE, diap1/thread and
bantam [102] . In mammalian cells, overexpression of YAP1 caused aberrant expression of genes associated
[103]
with cell proliferation, anti-apoptosis, survival and migration, such as CTGF, CCND1, ITGB2 and BCL2L1 .
Analysis on 177 HCC samples by immunohistochemistry, Western blot analysis and RT-PCR showed
that approximately 62% of both YAP protein and mRNA were upregulated as compared to adjacent non-
tumour tissues [104] . The YAP proteins were mainly accumulated in the tumour nucleus. In an independent
study, Zhao et al [101] also reported YAP overexpression in 63 of the 115 HCC samples tested by tissue
microarray. Similar results were reported in non-small lung cell cancer, suggesting that YAP may have broad
implications in different solid cancers [105] . Importantly, YAP expression was associated with poorer tumour
differentiation, high serum AFP level and lower overall survival rate, indicating that it may be used as an
independent prognostic marker [104] .

Both YAP and transcriptional co-activator with PDZ-binding motif (TAZ) are downstream effectors of
Hippo pathway. Hayashi et al [106] reported that knocking down TAZ, under normal condition, inhibited cell
growth in HCC. However, treating the TAZ knockdown cells with 5-fluorouracil induced YAP expression
that conferred chemoresistance. The drug resistance was not observed when both TAZ and YAP were
knockdown, suggesting that a shift to predominantly YAP expression when TAZ was depleted led to
chemoresistance and tumourigenecity. The authors concluded that targeting both YAP and ZAP is essential
for a complete anti-tumour response. Given that YAP expression is an early event in HCC tumourigenesis
and its expression is critical to chemoresistance and proliferation of malignant hepatocytes, YAP is a
promising HCC target for therapeutic intervention.

The oncogenic activity of YAP depends on its interaction with transcriptional enhancer activation domain
family member 1 (TEAD1) that resides in the nucleus and therefore, disrupting YAP-TEAD1 interaction is