Zhu et al.

Biomarker Research 2013, 1:10

http://www.biomarkerres.org/content/1/1/10

REVIEW Open Access

Biomarkers for hepatocellular carcinoma:

progression in early diagnosis, prognosis, and
personalized therapy
Kai Zhu1,2, Zhi Dai1,2 and Jian Zhou1,2,3*

Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Currently, surgical
resection, liver transplantation, and local ablation are considered curative therapeutic practices for HCC. The
diagnosis of HCC without pathologic confirmation is achieved by analyzing serum alpha-fetoprotein (AFP) levels
combined with imaging techniques, including ultrasonography, magnetic resonance imaging, and computerized
tomography. Although progress has been made in the diagnosis and management of HCC, its prognosis remains
dismal. Various new technologies have identified numerous novel biomarkers with potential diagnostic as well as
prognostic value, including Dickkopf-1 and Golgi protein 73. These biomarkers not only help in the early diagnosis
and prediction of prognosis, but also assist in identifying potential targets for therapeutic interventions. In this
article, we provide an up-to-date review of the biomarkers that are used for early diagnosis, prognosis prediction,
and personalized treatment of HCC.
Keywords: Hepatocellular carcinoma, Early diagnosis, Prognosis, Biological markers

Introduction oncogene addictions have been observed in HCC, which

Hepatocellular carcinoma (HCC) is one of the most is a complex disease with a variety of underlying patho-
frequently diagnosed cancers worldwide. The disease is genic anomalies caused by multiple risk factors. The
predominant in Asia and Africa, but its incidence is lack of ideal biomarkers for HCC diagnosis, prognosis,
steadily increasing throughout the rest of the world and therapy has posed a major challenge to HCC
[1]. Most HCC develop in patients with a history of management.
chronic hepatitis or cirrhosis in which there is continuous With advances in the understanding of tumor biol-
inflammation and regeneration of hepatocytes. Unlike ogy, interest in identifying molecular biomarkers of
other solid malignancies, the coexistence of inflammation HCC has increased. Over the last decade, a number of
and cirrhosis makes the early diagnosis and prognostic as- new cutting-edge technologies such as next-generation
sessment of HCC much more difficult. This complication sequencing [4,5] and microarray technologies [6-8]
highlights the need to identify valuable biomarkers for the have emerged, leading the search for biomarkers into a
diagnosis and treatment of HCC. new era of “omics” [9,10]. Using these technologies, it
The proliferation and survival of cancer cells require a is now quite easy to examine a whole tumor genome
process called oncogene addiction, which is the activa- (including copy number variations, loss of heterogeneity,
tion of specific oncogenes and inactivation of specific aneuploidy, single nucleotide polymorphism) [11-14],
tumor suppressors, such as Rb1 in retinoblastoma [2] transcriptome [15,16], proteome [17,18], epigenome
and BRCA1 in breast cancer [3]. However, no specific [19,20], metabolome [21-23], and miRNA profile [24,25],
and the analysis of tens of thousands of molecular targets
* Correspondence: [email protected] has become affordable and operable. Currently, numerous
1
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai
200032, China
circulating markers and tissue markers have been identi-
2
Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, fied [17,26-30]; however, few biomarkers are acceptable
Ministry of Education, Shanghai 200032, China for clinical utility because of their low predictive accuracy
Full list of author information is available at the end of the article

© 2013 Zhu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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and/or high cost. Here, we provide an up-to-date review beta-catenin in HCC cells via the Wnt/beta-catenin
of the biomarkers that are used for early diagnosis, signaling pathway [42].
prognosis, and personalized treatment of HCC. Recently, Shen et al. [41] reported that serum DKK1 is
a promising candidate for HCC diagnosis. The authors
Review retrospectively assessed serum DKK1 in 1284 patients
Biomarkers for early diagnosis (633 with HCC, 171 with chronic HBV infection, 168
The diagnosis of HCC without pathologic confirmation with cirrhosis, and 312 healthy controls) and found that
can be achieved by assessing the serum alpha-fetoprotein DKK1 has better diagnostic value for HCC than does
(AFP) level combined with imaging techniques, including AFP, especially for patients with AFP-negative and early
ultrasonography, magnetic resonance imaging, and stage HCC. Combined testing of serum DKK1 and AFP
computerized tomography [31,32]. However, improve- concentrations improved diagnostic accuracy for HCC
ment in early diagnosis is still needed because only 44% versus all controls compared with either test alone.
of the patients are diagnosed at a localized disease stage, Nevertheless, DKK1 is not overly specific for HCC diag-
and only 30% of patients with HCC are candidates for nosis, and a recent study reported that serum DKK1
potentially curative treatments at the time of diagnosis was also elevated in patients with intrahepatic cholan-
[33]. Thus, the discovery of an effective, reliable tool for giocarcinoma [43].
early diagnosis of HCC to increase the number of
patients who are suitable for curative treatment will play Golgi protein 73 (GP73) GP73 is a 73 kDa trans-
a pivotal role in improving HCC patients’ prognosis. membrane glycoprotein that normally resides within the
A marker for early diagnosis would meet the follow- Golgi complex. It is expressed in normal biliary epithe-
ing requirements: first, it should achieve high accuracy, lial cells whereas normal hepatocytes do not express this
which would increase the probability of a diagnosis protein, and its expression is significantly increased in
being made prior to spread and thus increase the cure liver diseases such as HCC [44].
rate; second, specimen collection for detecting the Serum GP73 is a valuable biomarker for patients with
marker should be easily operable and non-invasive; HCC [45,46]. Mao et al. [46] compared serum GP73 and
and third, the cost-effectiveness should be considered AFP in 4217 participants, including 1690 healthy adults,
[34]. Tumor tissue-oriented markers are not highly 337 HBV carriers, 512 patients with cirrhosis, 789
practical because not all tumor tissues can be obtained patients with HCC, 61 patients with other malignant
at an early stage and the invasive procedure may cause liver lesions, 206 patients with benign liver lesions and
spread of tumor cells. Biomarkers from body fluids 622 patients with 14 non-liver cancers. The sensitivity
such as serum, plasma, urine, and bile are suitable and specificity of serum GP73 for HCC were 74.6% and
candidates for early diagnosis of HCC because they are 97.4%, respectively, compared with 58.2% and 85.3% for
easily accessible [35]. In the following section, we list AFP. The GP73 level significantly increased in patients
some important circulating (serum or plasma) markers with HCC compared with healthy controls, decreased
for early diagnosis of HCC. following surgical resection of HCC lesions and
increased with tumor recurrence. Although the control
group included HBV carriers, this group lacked patients
Protein with chronic hepatitis, whereas most HCC patients have
Since AFP was discovered in the serum of HCC hepatitis.
patients in 1964 [36], it has been regarded as the most
useful serum protein thus far for patients at risk for Protein induced by vitamin K absence or antagonist
HCC [37-39]. However, its sensitivity for detecting II (PIVKA-II) PIVKA-II, an abnormal prothrombin
HCC ranges between 25%-60% [39,40], and its specificity discovered in 1984, has been widely proposed to be a
is also low because serum AFP can also be detected in useful HCC biomarker [47]. Takikawa et al. [48] mea-
patients with cirrhosis (11%-47%) and chronic hepatitis sured plasma levels of PIVKA-II and AFP in 628
(15%-58%). patients with various diseases, including 253 patients
In addition to AFP, more than 20 serum proteins with liver cirrhosis and 116 patients with HCC.
have clinical significance in early diagnosis of HCC PIVKA-II was detected in 54.3% of patients with HCC,
[10,41], among which several proteins are proved to and the concentration showed a positive correlation
have advantages over AFP. with the tumor size. As a screening test for detecting
HCC, PIVKA-II yielded sensitivity and specificity
DKK1 DKK1 belongs to a family of secreted proteins values (52.8% and 98.8%, respectively) that were com-
that play an important role in HCC progression through parable with AFP. Beale et al. [49] assessed AFP and
the promotion of cytoplasmic/nuclear accumulation of PIVKA-II levels in pre-treatment serum samples from
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50 patients with HCC, and the combination of serum TACE [61,62], PIVKA-II and VEGF for radiofrequency
AFP and PIVKA-II was better for detecting HCC than ablation (RFA) [63,64], and serum AFP and HBeAg for
using either AFP or PIVKA-II alone. percutaneous ethanol injection (PEI) [65-67].

Nucleic acids Biomarkers for surgical treatment

Nucleic acids, including DNA, RNA, and nucleosomes, Surgical treatment offers a potentially curative option
can be detected in the circulation of patients with for HCC patients, but patients’ outcomes are varied due
HCC, and changes in their levels have been associated to differing tumor characteristics. Additionally, the
with tumor burden and progression of malignancy exact biology of HCC remains poorly understood, thus
[50]. In the past decade, circulating nucleic acids have making prediction of outcome after surgical resection
been extensively studied with regard to their diagnostic very difficult. The prognosis of HCC patients does not
significance [51-54]. For instance, plasma AFP mRNA simply reflect the size and number of the tumors;
[28,55] is considered to be a diagnostic marker for instead, prognosis is affected by a complex interplay
HCC. Accumulating evidence has shown that microRNAs between known and unknown factors, including tumor
(miRNAs) play important roles in cancer initiation, biology, patient condition, etc. [35]. Thus, the ability to
propagation, and progression [56-58]. MiRNA deregula- predict which patients have a poor prognosis would help
tion occurs at early stages of HCC and increases to assign risk and guide surgery and other treatments.
throughout the various steps of hepatocarcinogenesis
[52]. There are multiple studies on the diagnostic func- Circulating biomarkers Circulating biomarkers are
tion of miRNA in HCC diagnosis [52,54,59]. However, still preferred for prognostic prediction because they
the diagnostic value of miRNAs is limited by one or are easily accessible. Serum AFP is commonly used for
more of the following factors: limited number of diagnosis and surveillance of HCC [37,39] and has been
screened miRNAs, small sample size, failure to differen- suggested as an independent indicator for prognosis. HCC
tiate HCC from hepatitis, and lack of independent patients with a high serum AFP level tend to have shorter
validation. survival [38,53].
Recently, we measured plasma miRNA expression pro- Other circulating factors such as Ang2 [53], VEGF
files (723 miRNAs) in a large cohort of 934 participants [53,68,69], HGF [70,71], and TGF-beta [72], are also in-
that included healthy individuals and patients with dependent factors for HCC prognosis. A recent study
chronic HBV infection, cirrhosis, or HBV-related HCC. proposed that plasma macrophage migration inhibitory
We identified a miRNA panel (miR-122, miR-192, miR- factor (MIF) levels have prognostic value in HCC
21, miR-223, miR-26a, miR-27a, and miR-801) that pro- patients. Plasma MIF levels have a significant association
vided high diagnostic accuracy for discriminating patients with overall survival (OS) and disease-free survival
with HCC from the healthy population (AUC = 0.941) and (DFS) of HCC patients, even in patients with normal
patients with chronic HBV (AUC = 0.842) or cirrhosis serum AFP levels and Tumor Node Metastasis (TNM)
(AUC = 0.884). This finding led to the conclusion that the stage I HCC [73].
plasma miRNA panel had considerable clinical value for Circulating tumor cells (CTCs) may reflect tumor
the early diagnosis of HCC and could help patients who aggressiveness and serve as a promising candidate for
might have otherwise missed the curative treatment predicting tumor recurrence and metastasis [74]. How-
window benefit from optimal therapy [54]. ever, their utility is limited due to the rarity of CTCs in
peripheral blood of the patients. Recent technical
Prognostic biomarkers advances have made it possible to detect CTCs; there-
Surgical resection, liver transplantation and local abla- fore, their clinical value has been tested in multiple
tion are considered curative therapeutic practices for tumor types, including breast cancer [75], lung cancer
HCC. Other modalities, such as targeted therapy and [76], and prostate cancer [77]. Sun et al. proved that
transarterial chemoembolization (TACE), are palliative EpCAM-positive CTCs may serve as a prognostic
treatments. Despite these curative or palliative treat- marker in HCC after curative resection [78].
ments, prognosis is still poor due to underlying liver
diseases and the unique biology of HCC. As a result, Tumor tissue biomarkers Research into tumor tissues
biomarkers that better predict patients who are at can provide direct biological information about the
higher risk of recurrence and poorer prognosis would tumors; thus, the search for tumor biomarkers is crucial.
help guide their treatment [26]. A plethora of HCC tumor cell-derived biomarkers with
A number of biomarkers have been reported to predict potential prognostic significance have been identified in
the outcome of these therapies, including CD151 and recent decades [9,17,26,35,79-81], but consensus could
CXCL5 for surgical treatment [27,60], AFP and LDH for not be reached.
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HCC-related proteins have been extensively explored systemic toxicity, increasing local antitumor effects,
for use in determining prognosis [9-11,82]. For instance, and improving survival [98,99]. However, there are
our previous study investigated CXCL5 (epithelial markedly diverse outcomes after TACE in terms of
neutrophil-activating peptide-78) expression in a large treatment response and survival. Therefore, identifying
cohort of 919 HCC patients. The results showed that markers that can predict TACE treatment outcomes
overexpression of CXCL5 was well correlated with before choosing this treatment option is an important
intratumoral neutrophil infiltration and that CXCL5 endeavor.
overexpression alone or in combination with the pres- The most promising prognostic candidates for TACE
ence of intratumoral neutrophils was an independent are circulating biomarkers. Some studies have reported
prognostic indicator for OS and cumulative recurrence that serum AFP [61], circulating nucleosomes [100],
in HCC patients [60]. In addition, our institute also blood neutrophil-to-lymphocyte ratio [101], and lactate
searched extensively for prognostic biomarkers in HCC dehydrogenase [62], are prognostic factors for TACE. As
patients undergoing liver transplantation [17,83]. By an example, Wang et al. [61] retrospectively studied the
investigating tumor tissues of 232 HCC patients, we survival of 441 HCC patients (including 139 patients
identified calpain small subunit 1 (Capn4) as an inde- with normal AFP levels and 302 patients with elevated
pendent prognostic factor for recurrence and survival in AFP levels) after TACE, and found that patients with
HCC patients after liver transplantation [17]. normal AFP levels had a better treatment response and
Cancer stem cells (CSCs) may play a pivotal role in prognosis after TACE than patients with elevated AFP
the progression of tumors [84,85]. CSCs represent the levels.
tumorigenic cells that generate tumors via the stem cell
processes of self-renewal and differentiation. CSCs may
Personalized therapy
persist in tumors as a distinct population and cause
The recent discovery of new therapeutic targets based
relapse and metastasis by giving rise to new tumors
on the molecular pathways that are involved in hepato-
[86]. Although the existence of CSCs in HCC is still
carcinogenesis has led to exciting results in targeted
controversial, several studies have demonstrated the
treatment of HCC patients. Investigators have attempted
clinical significance of CSC markers in HCC patients
to select therapeutic options for patients according to
[10,79]. These markers include CD90 [87], CD133 [29],
their tumor’s molecular profile, and this treatment
CD13 [88], and EpCAM [89].
modality will pave the way for personalized treatment of
The role of the microenvironment surrounding tumor
HCC.
cells for the initiation and progression of HCC is be-
coming increasingly clear [30,90-92]. The tumor micro-
environment, also named the tumor stroma, includes Targeted therapy
the extracellular matrix (ECM) and all other non-tumor Targeted therapy that specifically inhibits molecular
cell types within a tumor tissue (e.g. endothelial cells, abnormalities has emerged as an effective therapeutic
fibroblasts, and cells of the immune system). Various option for malignancies [102,103]. Small molecule
tumor stroma-associated factors, such as regulatory T tyrosine kinase inhibitors have great potential for the
cells (Tregs) [93], macrophage colony-stimulating factor treatment of HCC through targeting several growth
(M-CSF) [94], macrophages [95], and hepatic stellate factors and their associated signaling pathways (e.g.
cells [96], have been investigated and exhibit significant EGF/EGFR, VEGF/VEGFR, IGF/IGFR, PDGF, FGF,
prognostic value. For instance, Budhu et al. [97] showed RAS/RAF/ERK/MAPK, PI3K/AKT/mTOR, Wnt/beta-
that a unique inflammation/immune response-related catenin) [104,105]. Currently, nearly 60 reagents are
signature in the venous metastasis-associated liver being investigated for treatment of HCC, but only
microenvironment coincides with elevated expression of sorafenib have been proven effective in patients with
M-CSF and can serve as a superior predictor of HCC advanced HCC [106].
venous metastases when compared with other clinical Sorafenib is an oral multi-kinase inhibitor that com-
prognostic parameters. petitively inhibits ATP binding to the catalytic domains
of various kinases, such as Raf kinase, VEGFR-2, -3, and
Biomarkers for TACE PDGFR, thereby increasing apoptosis and decreasing
Although patients with early stage HCC have the angiogenesis and cell proliferation [79,106,107]. How-
chance to undergo curative treatment, most HCC ever, no specific marker can guide the use of sorafenib
patients are still diagnosed at a late stage when curative in HCC; in contrast, HER2 and EGFR expression can
treatment is no longer applicable. For these patients, positively predict the therapeutic response rate of tras-
based on randomized, controlled clinical trials, TACE tuzumab in breast cancer and cetuximab in non-small
may be an effective treatment option for reducing cell lung cancer, respectively.
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Other oral tyrosine-kinase inhibitors including suniti- Abbreviations

nib, linifanib, brivanib, and regorafenib block a number HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein; GP73: Golgi protein
73; PIVKA-II: Protein induced by vitamin K absence or antagonist II;
of angiogenesis-related signaling pathways, such as miRNA: microRNA; TACE: Transarterial chemoembolization;
VEGFR, PDGFR, and FGFR [35,104,107]. Although RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection;
many clinical trials have been discontinued because of MIF: Migration inhibitory factor; OS: Overall survival; DFS: Disease-free survival;
TNM: Tumor Node Metastasis; CTC: Circulating tumor cell; Capn4: Calpain
poor effectiveness or severe adverse effects, these small subunit 1; CSC: Cancer stem cell; ECM: Extracellular matrix;
approaches provide critical insight into the mechanisms Treg: Regulatory T cell; M-CSF: Macrophage colony-stimulating factor.
of targeted therapy for HCC and may finally allow us to
optimize the current therapies for this fatal disease. Competing interests
The authors declare that they do not have anything to disclose regarding
funding from industries or conflict of interest with respect to this manuscript.

Interferon-alpha Authors’ contributions

Interferon-alpha is a multifunctional cytokine that post- ZK drafted the manuscript. All authors read and approved the final
pones recurrence of HCC and improves OS in HCC manuscript.

patients after curative resection [108-110]. However, the

Grant support
benefit of interferon-alpha therapy is usually modest be- This study was jointly supported by the National Key Sci-Tech Special Project
cause it is not effective for all patients, and it is difficult of China (Grant No. 2012ZX10002-016), National Science Fund for
to determine which patients will respond well to Distinguished Young Scholars (81225019) and National Natural Science
Funds of China (No. 812250125; No. 81172277; No. 81272724).
interferon-alpha [108,111]. A recent study analyzed the
miRNA profiles of 455 patients with HCC who had Author details
1
undergone curative tumor resection and assessed the Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai
200032, China. 2Key Laboratory of Carcinogenesis and Cancer Invasion,
association of the miRNA profiles with survival and Fudan University, Ministry of Education, Shanghai 200032, China. 3Shanghai
response to therapy with interferon-alpha. The study Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan
showed that HCC patients whose tumors express low University, Shanghai 200032, China.
levels of miR-26 have a better response to interferon- Received: 27 October 2012 Accepted: 2 February 2013
alpha therapy than patients with high levels, suggesting Published: 5 February 2013
that miR-26 expression status could be used as a
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