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Page 8 of 14 Chia et al. Hepatoma Res 2019;5:9 I http://dx.doi.org/10.20517/2394-5079.2018.112

believed to have anti-cancer efficacy in YAP positive tumours [107] . YAP-like peptides occupying the interface
3 on YAP/TEAD complex were shown able to block YAP-TEAD1 interaction [108] . Small-molecule inhibitors
(SMIs) targeting the same interface were recently shown to suppress the expression of YAP target genes [109] .
Whether these peptides or SMIs would inhibit tumour growth in vivo however remains to be investigated.

Trop2
Trop2, also known as tumour-associated calcium signal transducer 2 (TACSTD2) or epithelial glycoprotein-1
antigen, is a calcium signal transducer encoded by the TACSTD2 gene located on human chromosome 1
(1p32.1). Trop2 is a cell surface glyprotein that is associated with regulation of cyclin D1 and protein kinase
C levels. Trop2 stimulates the expression of cyclin D1 and cyclin E via the mitogen-activated protein kinase/
extracellular signal-regulated kinase (MAPK/ERK) pathway to promote cell proliferation [110] . Numerous
reports have confirmed that Trop2 is an oncogene associated with tumour development, progression
and metastasis in various cancers, including pancreatic cancer [111] , squamous cell carcinoma [112] , gastric
carcinoma [113] , hilar cholangiocarcinoma [114] , colorectal cancer [115] , cervical cancer [116] , ovarian carcinoma [117] ,
gallbladder cancer [118] and breast cancer [119] . Unsurprisingly, Trop2 overexpression is often associated with
poor cancer prognosis. A recent gene network analytic study found aberrant expression of Trop2 in HCC [120] .
Given that Trop2 is an oncogene in many cancers, it is speculated that it may be a potential biomarker
candidate and a therapeutic target for HCC.

VASN
VASN is a cell surface and secreted protein that modulates the arterial response to injury by inhibiting the
TFG-β signaling pathway [121,122] . It was identified as a potential HCC biomarker using a subtractive EMSA-
SELEX strategy from AFP negative serum of HCC patients with secondary metastasis [123] . VASN expression
can be detected in aorta, kidney, placenta, brain, heart, liver, lung and skeletal muscle tissues. It was highly
expressed in HCC samples (n = 100) but not in normal liver (n = 97) or hepatitis samples (n = 129), as verified
by both Western blotting and quantitative PCR. This high VASN expression appeared to be negatively
regulated by microRNAs miR145 and miR146a. Downregulation of these microRNAs led to overexpression
of VASN, which promoted cell proliferation and migration and inhibited apoptosis. As a membrane protein,
VASN has the potential to be a therapeutic target.

Osteopontin
Osteopontin (OPN), a matrix glycoprotein secreted by a wide variety of cell types, has also emerged as a
biomarker with diagnostic potential [124] . Plasma level of OPN in patients with HCC was significantly higher
than in or healthy subjects or patients with chronic liver diseases [125] . In a prospective study on 22 patients
who developed HCC during follow-up, OPN was elevated in plasma one year before cancer diagnosis [126] .
A meta-analysis on 12 published studies showed that the sensitivity in HCC diagnosis was higher than
[127]
that of AFP (OPN, 0.813; AFP, 0.639) . Plasma OPN could be used to differentiate HCC from other non-
malignant liver diseases including chronic hepatitis C, cirrhosis, and nonalcoholic fatty liver disease [128] .
Importantly,serum OPN was associated with dismal overall survivals of patients with HCC with a hazard
ratio of 2.38 [129] .

In addition to its diagnostic value, OPN can be a potential therapeutic target for HCC treatment. Antiviral
therapy suppressed early progression of hepatitis B-related HCC by modulating the expression of OPN in
patients [130] . Knockdown of OPN using RNA interference suppressed in vivo growth and lung metastasis
of liver cancer xenograft in mice [131] . Monoclonal antibodies (mAbs) against OPN have been reported to
demonstrate anti-cancer effects in animal models. An antibody named AOM1, which abrogated the integrin
binding of OPN, was illustrated to suppress the in vivo of Kras-mutant non-small cell lung adenocarcinoma
in mice [132] . Hu1A12, another OPN mAb that bound to the calcium binding domain of OPN, was
demonstrated to inhibit primary tumor growth and spontaneous metastasis in a mouse lung metastasis