AFP

Gene Summary

Gene:AFP; alpha fetoprotein
Aliases: AFPD, FETA, HPAFP
Location:4q13.3
Summary:This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. Alpha-fetoprotein expression in adults is often associated with hepatoma or teratoma. However, hereditary persistance of alpha-fetoprotein may also be found in individuals with no obvious pathology. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin genes are present in tandem in the same transcriptional orientation on chromosome 4. Alpha-fetoprotein is found in monomeric as well as dimeric and trimeric forms, and binds copper, nickel, fatty acids and bilirubin. The level of alpha-fetoprotein in amniotic fluid is used to measure renal loss of protein to screen for spina bifida and anencephaly. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:alpha-fetoprotein
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • SOXD Transcription Factors
  • Gene Expression
  • Proportional Hazards Models
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Down-Regulation
  • Chromosome 4
  • Serpins
  • Subtraction Technique
  • Follow-Up Studies
  • Hepatocellular Carcinoma
  • Genetic Vectors
  • DNA Methylation
  • Precancerous Conditions
  • Liver Cancer
  • Hep G2 Cells
  • Gene Expression Profiling
  • Neoplasm Proteins
  • Disease Progression
  • Radiation Tolerance
  • AFP
  • RTPCR
  • Liver Cirrhosis
  • Promoter Regions
  • Genetic Therapy
  • Western Blotting
  • Immunohistochemistry
  • Apoptosis
  • Staging
  • Recurrence
  • Mice, Inbred BALB C
  • ROC Curve
  • Genotype
  • Cell Proliferation
  • MicroRNAs
  • RHOA
  • Neoplasm Invasiveness
  • Liver
  • Neoplasm Recurrence, Local
  • Adolescents
  • Case-Control Studies
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AFP (cancer-related)

Ma X, Wang X, Yang C, et al.
DANCR Acts as a Diagnostic Biomarker and Promotes Tumor Growth and Metastasis in Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(12):6389-6398 [PubMed] Related Publications
BACKGROUND: Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is considered to be an oncogene in many cancer types. However, the role of DANCR in diagnosis and progression of hepatocellular carcinoma (HCC) is still unknown.
PATIENTS AND METHODS: In this study, 146 participants including healthy volunteers (HVs) and patients with chronic hepatitis B (CHB), cirrhosis and HCC were recruited.
RESULTS: Firstly, quantitative reverse transcription-PCR analysis showed that DANCR was up-regulated in tumor tissues and plasma of patients with HCC, and its expression was highly correlated with microvascular and liver capsule invasion of HCC. Receiver operating characteristic analysis showed that plasma DANCR exhibited significantly increased discriminatory power for differentiating patients with HCC from HVs and non-HCC patients compared to alpha fetoprotein, which has been used as a biomarker for HCC diagnosis. Furthermore, knockdown of DANCR repressed the β-catenin pathway and inhibited HCC cell proliferation and metastasis both in vitro and in vivo.
CONCLUSION: This study revealed, for the first time, the importance of DANCR in clinical diagnosis and disease progression of HCC.

Allen JC, Nault JC, Zhu G, et al.
The transcriptomic G1-G6 signature of hepatocellular carcinoma in an Asian population: Association of G3 with microvascular invasion.
Medicine (Baltimore). 2016; 95(47):e5263 [PubMed] Free Access to Full Article Related Publications
In this study, a transcriptomic group classification based on a European population is tested on a Singapore cohort. The results highlight the genotype/phenotype correlation in a Southeast Asian population. The G1-G6 transcriptomic classification derived from hepatocellular carcinoma (HCC) resected from European patients, robustly reflected group-specific clinical/pathological features. We investigated the application of this molecular classification in Southeast Asian HCC patients.Gene expression analysis was carried out on HCC surgically resected in Singapore patients who were grouped into G1-G6 transcriptomic categories according to expression of 16 predictor genes (illustrated in Supplementary Table 1, http://links.lww.com/MD/B413 and Supplementary Fig. 1, http://links.lww.com/MD/B413) using quantitative reverse transcription polymerase chain reaction (RT-PCR). Univariate and multivariate polytomous logistic regression was used to investigate association between clinical variables and pooled transcriptomic classes G12, G3, and G456.HCC from Singapore (n = 82) were distributed (%) into G1 (13.4), G2 (24.4), G3 (15.9), G4 (24.4), G5 (14.6), and G6 (7.3) subgroups. Compared to the European data, the Singapore samples were relatively enriched in G1-G3 versus G4-G6 tumors (53.7% vs 46.3%) reflecting the higher proportion of hepatitis B virus (HBV) patients in Singapore versus Europe samples (43% vs 30%). Pooled classes were defined as G12, G3, and G456. G12 was associated with higher alpha-fetoprotein (AFP) concentrations (OR = 1.69, 95% CI: 1.30-2.20; P < 0.0001) and G3 with microvascular invasion (OR = 4.91, 95% CI: 1.06-24.8; P = 0.047).The European and Singapore cohorts were generally similar relative to associations between transcriptomic groups and clinical features. This lends credence to the G1-G6 transcriptomic classifications being applicable regardless of the ethnic origin of HCC patients. The G3 group was associated with microvascular invasion and holds potential for investigation into the underlying mechanisms and selection for therapeutic clinical trials.

Han C, Yu L, Liu X, et al.
ATXN7 Gene Variants and Expression Predict Post-Operative Clinical Outcomes in Hepatitis B Virus-Related Hepatocellular Carcinoma.
Cell Physiol Biochem. 2016; 39(6):2427-2438 [PubMed] Related Publications
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a lethal disease with nearly equal morbidity and mortality. Thus, the discovery and application of more useful predictive biomarkers for improving therapeutic effects and prediction of clinical outcomes is of crucial significance.
METHODS: A total of 475 HBV-related HCC patients were enrolled. Ataxin 7 (ATXN7) single nucleotide polymorphisms (SNPs) were genotyped by Sanger DNA sequencing after PCR amplification. The associations between ATXN7 SNPs and mRNA expression with the prognosis of HBV-related HCC were analyzed.
RESULTS: In all, rs3774729 was significantly associated with overall survival (OS) of HBV-related HCC (P = 0.013, HR = 0.66, 95% CI: 0.48-0.94). And patients with the AA genotype and a high level of serum alpha fetoprotein (AFP) had significantly worse OS when compared to patients with AG/GG genotypes and a low level of AFP (adjusted P = 0.007, adjusted HR = 1.83, 95% CI = 1.18-2.82). Furthermore, low expression of ATXN7 was significantly associated with poor recurrence-free survival (RFS) and OS (P = 0.007, HR = 2.38, 95% CI = 1.27-4.45 and P = 0.025, HR = 1.75, 95% CI = 1.18-2.62).
CONCLUSION: ATXN7 may be a potential predictor of post-operative prognosis of HBV-related HCC.

Zekri AN, Youssef AS, El-Desouky ED, et al.
Serum microRNA panels as potential biomarkers for early detection of hepatocellular carcinoma on top of HCV infection.
Tumour Biol. 2016; 37(9):12273-12286 [PubMed] Related Publications
The identification of new high-sensitivity and high-specificity markers for hepatocellular carcinoma (HCC) is essential. We aimed at identifying serum microRNAs (miRNAs) as potential biomarkers for early detection of HCC on top hepatitis C virus (HCV) infection. We investigated serum expression of 13 miRNAs in 384 patients with HCV-related chronic liver disease (192 with HCC, 96 with liver cirrhosis (LC), and 96 with chronic hepatitis C (CHC)) in addition to 96 healthy participants enrolled as a control group. The miRNA expression was performed using real-time quantitative PCR-based SYBR Green custom miRNA arrays. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of miRNA panels for early detection of HCC. Using miRNA panel of miR-122, miR-885-5p, and miR-29b with alpha fetoprotein (AFP) provided high diagnostic accuracy (AUC = 1) for early detection of HCC in normal population while using miRNA panel of miR-122, miR-885-5p, miR-221, and miR-22 with AFP provided high diagnostic accuracy (AUC = 0.982) for early detection of HCC in LC patients. However, using miRNA panel of miR-22 and miR-199a-3p with AFP provided high diagnostic accuracy (AUC = 0.988) for early detection of HCC in CHC patients. We identified serum miRNA panels that could have a considerable clinical use in early detection of HCC in both normal population and high-risk patients.

Ma S, Ding M, Li J, et al.
Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma: clinical outcomes and prognostic factors.
J Cancer Res Clin Oncol. 2017; 143(1):131-142 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate the clinical outcomes of ultrasound-guided percutaneous microwave ablation (US-guided PMWA) for the treatment of hepatocellular carcinoma (HCC) with the analysis of prognostic factors.
MATERIALS AND METHODS: The treatment and survival parameters of 433 patients with HCC (≤10 cm), who met the inclusion criteria and had received US-guided PMWA in Renji Hospital from July 2010 to November 2014, were retrospectively analyzed. Imaging examination (contrast-enhanced CT or MR) and tumor markers (AFP and CA199) 1 month after MWA were used to evaluate the efficacy of US-guided PMWA. SPSS software was used to perform all statistical analyses.
RESULTS: The initial complete ablation (CA) rate was 94.9 % (411/433). Twenty-two patients with incomplete ablation received repeat PMWA, and the total CA rate was up to 98.6 % (427/433). Multiple tumor number, tumor >5 cm in diameter, and higher serum AFP level (>20 ng/ml) were significant unfavorable prognosticators of progression-free survival (PFS). The cumulative 1-, 2-, and 3-year overall survival (OS) rates were 83.5, 66.1, and 58.7 %, respectively (median: 43 months). Tumor >5 cm in diameter and serum AFP >400 ng/ml were significant unfavorable prognosticators of OS.
CONCLUSIONS: PMWA is well tolerated in HCC patients and capable of offering high CA rate. Tumor number, tumor size, and AFP level were significant prognosticators of patients' PFS, whereas tumor size and AFP level were significant prognosticators of OS.

Xu L, Zhang M, Zheng X, et al.
The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma.
J Cancer Res Clin Oncol. 2017; 143(1):17-27 [PubMed] Related Publications
PURPOSE: Circular RNAs (circRNA) represent a novel class of widespread and diverse endogenous RNAs that regulate gene expression in mammals. microRNA-7 (miR-7) is a well-demonstrated suppressor of hepatocellular carcinoma (HCC). Recent studies have showed that one such circRNA, ciRS-7 (also termed as Cdr1as) was the inhibitor and sponge of miR-7 in the embryonic zebrafish midbrain and islet cells. However, the relationships among ciRS-7, miR-7 and clinical features of HCC remain to be clarified.
METHODS: Expression levels of ciRS-7, miR-7 and three miR-7-targeted mRNAs in 108 pairs of HCC and their matched non-tumor tissues were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The protein production of these three miR-7-targeted mRNAs was further verified by Western blot. The relationship between ciRS-7 level and clinicopathological features as well as the recurrence of HCC patients was analyzed. The univariate and multivariate logistic regression analyses were used to detect the risk factors of hepatic microvascular invasion (MVI). The correlation among ciRS-7, miR-7 and miR-7-targeted mRNAs was evaluated using Spearman's correlation test.
RESULTS: There was no significant difference of ciRS-7 expression levels between the HCC tissues and the matched non-tumor tissues (0.67 ± 1.49 vs. 0.44 ± 0.45, p = 0.13), and the ciRS-7 levels in more than half of HCC tissues (65 out of 108, 60.2 %) were down-regulated when compared with their matched non-tumor tissues. However, the expression of ciRS-7 was significantly correlated with the following three clinicopathological characteristics of HCC patients: age <40 years (p = 0.02), serum AFP ≥400 ng/µl (p < 0.01) and hepatic MVI (p = 0.03). Meanwhile, up-regulated ciRS-7 expression was not only an independent risk factor of hepatic MVI but also had a capable predictive ability for MVI (AUC = 0.68, p = 0.001) at the cut-off value of 0.135. Furthermore, the expression of ciRS-7 in HCC tissues with concurrent MVI was inversely correlated with that of miR-7 (r = -0.39, p = 0.007) and positively related with that of two miR-7-targeted genes [PIK3CD (r = 0.55, p < 0.001) and p70S6K (r = 0.34, p = 0.021)]. In addition, the median recurrent time of patients from higher ciRS-7 level group was shorter than that of lower ciRS-7 group (18 vs. 25 months), but no significant difference was observed (p = 0.38).
CONCLUSIONS: The expression levels of ciRS-7 were comparable between HCC and matched non-tumor tissues. However, the highly ciRS-7 expression in HCC tissues was significantly correlated with hepatic MVI, AFP level and younger age and thus partly related with the deterioration of HCC. Especially, ciRS-7 was one of the independent factors of hepatic MVI. These data suggested that ciRS-7 may be a promising biomarker of hepatic MVI and a novel therapy target for restraining MVI.

He Q, Yao CL, Li L, et al.
Targeted gene therapy and in vivo bioluminescent imaging for monitoring postsurgical recurrence and metastasis in mouse models of liver cancer.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
We investigated the effects of combined targeted gene therapy on recurrence and metastasis after liver cancer resection in nude mice. Twenty BALB/C mice were randomly divided into control and treatment groups with 10 mice in each group and a male/female ratio of 1:1. Luciferase gene-labeled human primary hepatic carcinoma cell line MHCC97-H was then used to prepare a carcinoma model. An optical in vivo imaging technique (OIIT) was used 10 days later to detect the distribution of tumor cells, followed by partial liver resection and gene therapy. In the treatment group, 100 mL phosphate-buffered saline (PBS) containing 1 x 1012 rAAV/AFP/IL-24 gene viral vectors was injected into liver sections and peritumoral posterior peritoneal tissues; in the control group, the same amount of PBS containing 1 x 1012 empty viral vectors was injected at the same sites. OIIT was then used to detect the in vivo tumor metastasis 21 days later. Luciferase gene-labeled human primary hepatic carcinoma cell line MHCC97-H successfully infected 20 nude mice, and OIIT showed that the two groups exhibited metastasis after local tumor resection, but there were more tumor cells in the control group (P < 0.05). rAAV/AFP/IL-24 gene therapy can inhibit recurrence after liver cancer resection.

Jing W, Luo P, Zhu M, et al.
Prognostic and Diagnostic Significance of SDPR-Cavin-2 in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2016; 39(3):950-60 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor worldwide. Due to the lack of early prediction marker, numerous patients were diagnosed in their late stage. The family of cavins plays important roles in caveolae formation and cellular processes. Cavin-2, one of the members of cavins, has been reported as a suppresser in cancers. In this study, we have investigated its expression pattern and clinical significance in HCC.
METHODS: RT‑qPCR was performed to detect the expression of cavin-2.
RESULTS: Cavin-2 was down-regulated in HCC and associated with tumor differentiation (r=-0.275, P=0.013) and tumor-node-metastasis (TNM) stage (r=-0.216, P=0.035). The Overall survival analysis showed that patients with lower cavin-2 expression had a relatively poor prognosis. Meanwhile, the multivariate analysis revealed that cavin-2 was an independent prognostic factor. The receiver operating characteristic curve analyses indicated that plasma cavin-2 presented a high accuracy (AUC=0.727, 0.865, 0.901) for diagnosing HCC cases from controls, hepatitis B and cirrhosis patients, respectively. Meanwhile, plasma cavin-2 showed a high sensitivity (88.4%, 89.9%) for detecting HCC with the serum α‑fetoprotein (AFP) levels below 200 ng/ml from those hepatitis B and cirrhosis cases.
CONCLUSION: Our data suggested that cavin-2 might be considered as a potential prognostic and diagnostic indicator in HCC.

Yu J, Han J, Zhang J, et al.
The long noncoding RNAs PVT1 and uc002mbe.2 in sera provide a new supplementary method for hepatocellular carcinoma diagnosis.
Medicine (Baltimore). 2016; 95(31):e4436 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver in adults worldwide. Several studies have demonstrated that long noncoding RNAs (lncRNAs) are involved in the development of various types of cancer, including HCC. These findings prompted us to examine the detectability of lncRNAs in blood samples from patients with HCC. In this study, we explored the expression levels of 31 cancer-related lncRNAs in sera from 71 HCC patients and 64 healthy individuals by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). We found that 25 lncRNAs could be detected in the serum and that 7 had significantly different expression levels. A 2-lncRNA signature (PVT1 and uc002mbe.2) identified by stepwise regression showed potential as a diagnostic marker for HCC. The area under the receiver operating characteristic (ROC) curve was 0.764 (95% CI: 0.684-0.833). The sensitivity and specificity values of this serum 2-lncRNA signature for distinguishing HCC patients from the healthy group were 60.56% and 90.62%, respectively. The diagnostic ability of the combination of the serum 2-lncRNA signature with alpha-fetoprotein (AFP) was much greater than that of AFP alone. The expression levels of the 2 lncRNAs were associated with clinical parameters including tumor size, Barcelona Clinic Liver Cancer (BCLC) stage, and serum bilirubin.

Ramesh V, Ganesan K
Integrative functional genomic analysis unveils the differing dysregulated metabolic processes across hepatocellular carcinoma stages.
Gene. 2016; 588(1):19-29 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease and the development of targeted therapeutics is still at an early stage. The 'omics' based genome-wide profiling comprising the transcriptome, miRNome and proteome are highly useful in identifying the deregulated molecular processes involved in hepatocarcinogenesis. One of the end products and processes of the central dogma being the metabolites and metabolic processes mediate the cellular functions. In recent years, metabolomics based investigations have revealed the major deregulated metabolic processes involved in carcinogenesis. However, the integrative analysis of the holistic metabolic processes with genomics is at an early stage. Since the gene-sets are highly useful in assessing the biological processes and pathways, we made an attempt to infer the deregulated cellular metabolic processes involved in HCC by employing metabolism associated gene-set enrichment analysis. Further, the metabolic process enrichment scores were integrated with the transcriptome profiles of HCC. Integrative analysis shows three distinct metabolic deregulations: i) hepatocyte function related molecular processes involving lipid/fatty acid/bile acid synthesis, ii) inflammatory processes with cytokine, sphingolipid & chondriotin sulphate metabolism and iii) enriched nucleotide metabolic process involving purine/pyrimidine & glucose mediated catabolic process, in hepatocarcinogenesis. The three distinct metabolic processes were found to occur both in tumor and liver cancer cell line profiles. Unsupervised hierarchical clustering of the metabolic processes along with clinical sample information has identified two major clusters based on AFP (alpha-fetoprotein) and metastasis. The study reveals the three major regulatory processes involved in HCC stages.

Peng R, Zhao GX, Li J, et al.
Auphen and dibutyryl cAMP suppress growth of hepatocellular carcinoma by regulating expression of aquaporins 3 and 9 in vivo.
World J Gastroenterol. 2016; 22(12):3341-54 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate whether the regulation of aquaporin 3 (AQP3) and AQP9 induced by Auphen and dibutyryl cAMP (dbcAMP) inhibits hepatic tumorigenesis.
METHODS: Expression of AQP3 and AQP9 was detected by Western blot, immunohistochemistry (IHC), and RT-PCR in HCC samples and paired non-cancerous liver tissue samples from 30 hepatocellular carcinoma (HCC) patients. A xenograft tumor model was used in vivo. Nine nude mice were divided into control, Auphen-treated, and dbcAMP-treated groups (n = 3 for each group). AQP3 and AQP9 protein expression after induction of xenograft tumors was detected by IHC and mRNA by RT-PCR analysis. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and histological evaluation were used to detect apoptosis of tumor cells, and the concentration of serum α-fetoprotein (AFP) was measured using RT-PCR and an ELISA kit.
RESULTS: The volumes and weights of tumors decreased significantly in the Auphen- and dbcAMP-treated mice compared with the control mice (P < 0.01). The levels of AQP3 were significantly lower in the Auphen treatment group, and levels of AQP9 were significantly higher in thedbcAMP treatment mice than in the control mice (P < 0.01). The reduction of AQP3 by Auphen and increase of AQP9 by dbcAMP in nude mice suppressed tumor growth of HCC, which resulted in reduced AFP levels in serum and tissues, and apoptosis of tumor cells in the Auphen- and dbcAMP-treated mice, when compared with control mice (P < 0.01). Compared with para-carcinoma tissues, AQP3 expression increased in tumor tissues whereas the expression of AQP9 decreased. By correlating clinicopathological and expression levels, we demonstrated that the expression of AQP3 and AQP9 was correlated with clinical progression of HCC and disease outcomes.
CONCLUSION: AQP3 increases in HCC while AQP9 decreases. Regulation of AQP3 and AQP9 expression by Auphen and dbcAMP inhibits the development and growth of HCC.

Lu S, Ma Y, Sun T, et al.
Expression of α-fetoprotein in gastric cancer AGS cells contributes to invasion and metastasis by influencing anoikis sensitivity.
Oncol Rep. 2016; 35(5):2984-90 [PubMed] Related Publications
α-fetoprotein (AFP) is a valuable tumor marker for many types of cancers, including primary gastric cancer (GC). However, the effects of AFP expression on the metastasis and anoikis sensitivity of GC remain unclear. The present study aimed to explore the role and possible mechanism of AFP in the invasion and metastasis of GC AGS cells, particularly in the anoikis sensitivity of AGS cells. In the present study, the expression of AFP in cultured AGS cells was assayed firstly by RT-PCR, western blotting and sequencing. Then, a specific AFP siRNA was applied to interfere with AFP expression and poly(2-hydroxyethyl methacrylate) (poly-HEMA) was used to block cell anchorage. The invasion and metastatic ability, and anoikis sensitivity detections were conducted based on Transwell chamber assay, anoikis assay kit and western blotting. Our results confirmed the expression of AFP in AGS cells. Then, we found that interference of AFP with siRNA attenuated the invasion and metastasis of AGS cells and induced a significant upregulation of E-cadherin and downregulation of N-cadherin expression (P<0.05). Cell apoptosis and anoikis were induced when cell anchorage was blocked by poly-HEMA treatment, which was exacerbated significantly when cells were exposed to AFP siRNA. Moreover, interference of AFP when cell anchorage was blocked enhanced the expression of the pro-apoptotic proteins Bax, caspase-3 and -9, and decreased the expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). In conclusion, the present study demonstrated that interference of AFP reduced AGS cell invasion and metastasis by enhancing anoikis sensitivity. The present study provides new insight for the treatment of GC and suggests AFP as a potential therapeutic target by regulating anoikis sensitivity.

Lin M, Huang J, Zhang D, et al.
Hepatoma-Targeted Radionuclide Immune Albumin Nanospheres: (131)I-antiAFPMcAb-GCV-BSA-NPs.
Anal Cell Pathol (Amst). 2016; 2016:9142198 [PubMed] Free Access to Full Article Related Publications
An effective strategy has been developed for synthesis of radionuclide immune albumin nanospheres ((131)I-antiAFPMcAb-GCV-BSA-NPs). In vitro as well as in vivo targeting of (131)I-antiAFPMcAb-GCV-BSA-NPs to AFP-positive hepatoma was examined. In cultured HepG2 cells, the uptake and retention rates of (131)I-antiAFPMcAb-GCV-BSA-NPs were remarkably higher than those of (131)I alone. As well, the uptake rate and retention ratios of (131)I-antiAFPMcAb-GCV-BSA-NPs in AFP-positive HepG2 cells were also significantly higher than those in AFP-negative HEK293 cells. Compared to (131)I alone, (131)I-antiAFPMcAb-GCV-BSA-NPs were much more easily taken in and retained by hepatoma tissue, with a much higher T/NT. Due to good drug-loading, high encapsulation ratio, and highly selective affinity for AFP-positive tumors, the (131)I-antiAFPMcAb-GCV-BSA-NPs are promising for further effective radiation-gene therapy of hepatoma.

Abdelgawad IA, Radwan NH, Hassanein HR
KIAA0101 mRNA expression in the peripheral blood of hepatocellular carcinoma patients: Association with some clinicopathological features.
Clin Biochem. 2016; 49(10-11):787-91 [PubMed] Related Publications
OBJECTIVES: The development of hepatocellular carcinoma (HCC) is multi-factorial, multi-step and involving many genes. Recent studies have revealed the involvement of KIAA0101 in HCC development and progression. KIAA0101 is involved in the regulation of DNA repair, cell cycle progression, and cell proliferation. This study aims to elucidate the clinicopathological significance of KIAA0101 mRNA expression in the whole blood of HCC patients.
DESIGN AND METHODS: This study was conducted on 77 patients with proven HCC who presented to the outpatient clinic at the National Cancer Institute - Cairo University over a period of 8 consecutive months. Thirty patients with cirrhosis and forty apparently healthy volunteers were included as control groups. Detection of KIAA0101 mRNA was done on whole blood collected on EDTA for all patients and control subjects using real-time PCR.
RESULTS: KIAA0101 mRNA was over-expressed in the HCC group compared to the control groups. Overexpression of KIAA0101 mRNA was significantly associated with distant metastasis, advanced stage, high serum alkaline phosphatase and low serum albumin levels. Both sensitivity and specificity of KIAA0101 mRNA were higher than those of AFP and CEA.
CONCLUSION: Being associated with some of the prognostic factors of HCC which reflect tumor progression; as advanced stage, distant metastasis, hypoalbuminemia and elevated serum alkaline phosphatase, together with its relatively high diagnostic performance; KIAA0101 mRNA might be nominated to play a probable role in the diagnosis and prognosis prediction of HCC. Further studies on a wider scale are recommended to confirm these results.

Zhou J, Ma P, Li J, et al.
Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-γ gene.
Mol Med Rep. 2016; 13(4):3197-205 [PubMed] Related Publications
Dendritic cell (DC)-based antigen-targeted immunotherapy may offer effective adjuvant therapy for hepatocellular carcinoma (HCC), in which cytotoxic T lymphocytes (CTLs) are key. However, in a number of cases, the activity of CTLs is completely inhibited due to the downregulated expression of major human leukocyte antigen (HLA) class I molecules by HCC cells. The aim of the present study was to overcome this issue. Hep3B cells were transduced by HCC‑specific recombinant adeno‑associated virus (rAAV) carrying human α‑fetoprotein promoter (AFPp) and the interferon‑γ (IFN‑γ) gene (rAAV/AFPp‑IFN‑γ). rAAV carrying the cytomegalovirus promoter (CMVp) and human α‑fetoprotein (AFP) gene (rAAV/CMVp‑AFP) was used to transduce professional antigen‑presenting DCs for the purpose of stimulating a CTL response. It was observed that transduction of DCs with rAAV/CMVp‑AFP resulted in: (i) AFP and interleukin‑12 expression; (ii) high expression levels of cluster of differentiation (CD)80, CD83, CD86, CD40, HLA‑death receptor and CD1a; (iii) T cell populations with marked IFN‑γ expression; (iv) a high percentage of CD69+/CD8+ T cells; and (v) the activity of CTLs against HLA‑A2‑expressing Hep3B cells. The transduction of Hep3B cells with rAAV/AFPp‑IFN‑γ resulted in: (i) IFN‑γ expression; (ii) upregulated expression of HLA‑A2; and (iii) an improved CTL response against HLA‑A2‑deficient Hep3B cells. rAAV/CMVp‑AFP‑transduced DCs elicited an AFP‑specific and HLA‑class I‑restricted CTL response against Hep3B cells. In conclusion, it was shown that the transduction of Hep3B with rAAV/AFPp-IFN-γ upregulated the expression of HLA-A2 and improved the sensitivity to CTL response.

Wang XC, Wang F, Quan QQ
Roles of XRCC1/XPD/ERCC1 Polymorphisms in Predicting Prognosis of Hepatocellular Carcinoma in Patients Receiving Transcatheter Arterial Chemoembolization.
Genet Test Mol Biomarkers. 2016; 20(4):176-84 [PubMed] Related Publications
OBJECTIVE: To investigate the potential prognostic roles of polymorphisms in the X-ray repair cross-complementing group 1 (XPCC1), xeroderma pigmentosum group D (XPD) and excision repair cross-complementing group 1 (ERCC1) genes for patients with hepatocellular carcinoma (HCC) receiving transcatheter arterial chemoembolization (TACE).
METHODS: Clinical data and blood samples from 308 HCC patients receiving TACE were collected between January 2010 and December 2013. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP) analyses was used to determine the genotypes of the XPCC1 (rs25487), XPD (rs13181) and ERCC1 (rs11615) genes. The relationships between the genotypes and the efficacy of TACE treatment were analyzed.
RESULTS: The XRCCI rs25487 polymorphism was associated with a favorable prognosis in HCC patients receiving TACE (p = 0.006), and patients carrying variant genotypes (A/A + G/A) were associated with significantly reduced risk of death compared with those with the wild genotype (G/G) (HR = 0.556; 95% CI = 0.354-0.874). These findings were supported by Kaplan-Meier survival curve analysis showing that median survival time for patients with A/A + G/A genotypes was significantly longer compared with those with the G/G genotype (11.2 month vs. 8.0 months; log rank p = 0.006). Stratified analyses revealed that A/A + G/A genotypes of XRCC1 rs25487 are associated with significantly reduced risk of death compared with the G/G genotype in patients grouped by tumor size, portal vein tumor thrombus (PVTT), alpha-fetoprotein (AFP) and TNM stage (all p < 0.05). The ERCC1 rs13181 and XPD rs11615 polymorphisms were not predictive of clinical outcome for HCC patients receiving TACE (both p > 0.05).
CONCLUSION: The XRCC1 rs25487 polymorphisms are prognostic for HCC patients receiving TACE. The ERCC1 and XPD polymorphisms had no relationship to the clinical outcomes.

Grimm D, Lieb J, Weyer V, et al.
Organic Cation Transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment.
BMC Cancer. 2016; 16:94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The polyspecific organ cation transporter 1 (OCT1) is one of the most important active influx pumps for drugs like the kinase inhibitor sorafenib. The aim of this retrospective study was the definition of the role of intratumoral OCT1 mRNA expression in hepatocellular carcinoma (HCC) as a biomarker in systemic treatment with sorafenib.
METHODS: OCT1 mRNA expression levels were determined in biopsies from 60 primary human HCC by real time PCR. The data was retrospectively correlated with clinical parameters.
RESULTS: Intratumoral OCT1 mRNA expression is a significant positive prognostic factor for patients treated with sorafenib according to Cox regression analysis (HR 0.653, 95%-CI 0.430-0.992; p = 0.046). Under treatment with sorafenib, a survival benefit could be shown using the lower quartile of intratumoral OCT1 expression as a cut-off. Macrovascular invasion (MVI) was slightly more frequent in patients with low OCT1 mRNA expression (p = 0.037). Treatment-induced AFP response was not associated with intratumoral OCT1 mRNA expression levels (p = 0.633).
CONCLUSIONS: This study indicates a promising role for intratumoral OCT1 mRNA expression as a prognostic biomarker in therapeutic algorithms in HCC. Further prospective studies are warranted on this topic.

Wubetu GY, Morine Y, Teraoku H, et al.
High NEK2 Expression Is a Predictor of Tumor Recurrence in Hepatocellular Carcinoma Patients After Hepatectomy.
Anticancer Res. 2016; 36(2):757-62 [PubMed] Related Publications
BACKGROUND/AIM: Better prognosis of cancer including hepatocellular carcinoma (HCC) remains unsatisfactory due to recurrence and chemoresistance. In this respect it is important to identify molecular targets specific to the disease in order to design effective therapeutic strategies. In the present study, we investigated the prognostic role of Never-in-mitosis-A-related kinase 2 (NEK2) in HCC.
MATERIALS AND METHODS: Fifty HCC patients who underwent hepatectomy were enrolled in the study. NEK2 gene and protein expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively.
RESULTS: Higher expression of NEK2 was detected in HCC tumoral compared to adjacent non-tumor tissues (p<0.001), and protein expression was also relatively high in tumor than corresponding non-tumor tissues. Furthermore, high NEK2 expression was positively correlated with hepatic venous invasion (p=0.047), des-gammacarboxy prothrombin (p=0.003), and alpha-fetoprotein (AFP) (p=0.024). Patients with high NEK2 expression had significantly poor recurrence-free survival (p=0.042) and early recurrence.
CONCLUSION: Overall, these results suggest that NEK2 could be a promising biomarker for HCC recurrence.

Xu Z, Cao C, Xia H, et al.
Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma.
Front Med. 2016; 10(1):52-60 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P = 0.044). Kaplan- Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCCspecific overall survival (HR, 2.799; 95% CI, 1.346-5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.

Jeon Y, Kim H, Jang ES, et al.
Expression profile and prognostic value of glypican-3 in post-operative South Korean hepatocellular carcinoma patients.
APMIS. 2016; 124(3):208-15 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) patients commonly experience poor overall survival (OS) and disease-free survival (DFS) after curative surgical resection. Glypican-3 (GPC3) has been suggested as a prognostic biomarker for post-operative survival. However, few to none of these studies have included South Korean patients. This study aimed to determine GPC3 expression rate, clinical correlation, and post-operative prognostic value in South Korean HCC patients who underwent curative surgical resection. Surgically resected tissues from 185 HCC patients were collected and assembled into tissue microarrays (TMAs), which were stained for GPC3 by immunohistochemistry. GPC3 expression rates were correlated with clinicopathological information, and survival analyses were performed to assess the prognostic value of GPC3. GPC3 expression was present in 153 patients (82.7%). GPC3-positive patients were younger with higher frequencies of microvascular invasion and higher AFP levels than GPC3-negative patients. There was no significant difference in survival between GPC3-negative and GPC3-positive patients. Based on multivariate analysis, GPC3 expression was not a prognostic marker for post-operative survival. In South Korean HCC patients, GPC3 expression was more frequent in HCCs with aggressive features, but it was not an independent prognostic biomarker.

Ghosh A, Ghosh A, Datta S, et al.
Hepatic miR-126 is a potential plasma biomarker for detection of hepatitis B virus infected hepatocellular carcinoma.
Int J Cancer. 2016; 138(11):2732-44 [PubMed] Related Publications
Controversies about the origin of circulating miRNAs have encouraged us to identify organ specific circulating miRNAs as disease biomarkers. To identify liver-specific miRNAs for hepatocellular carcinoma (HCC), global expression profiling of miRNAs in liver tissue of HBV-HCC and HBV-control with no or mild fibrosis was evaluated. A total of 40 differentially expressed miRNAs were identified in HCC. Among ten highly altered miRNAs, six miRNAs were successfully validated in tissues, whereas only two miRNAs, miR-126 and miR-142-3p showed increased expression in plasma of HBV-HCC compared to HBV-non-HCC patients. Subsequently, ROC curve analysis revealed that neither miR-126 nor miR-142-3p performed better than AFP in discriminating HCC from non-HCC while combination of each with AFP showed significantly higher efficiency rather than AFP alone (AUC: 0.922, 0.908 vs. 0.88; sensitivity: 0.84, 0.86 vs. 0.82 and specificity: 0.92, 0.94 vs. 0.86 respectively). Interestingly, triple combination of markers (miR-126 + miR-142-3p + AFP) showed no additive effect on efficiency (AUC: 0.925) over the dual combination. Again, the expression of only miR-126 was noticed significantly higher in HBV-HCC patients with low-AFP [<250 ng/ml] compared to either non-HCC or liver cirrhosis (AUC: 0.77, 0.64, respectively). Furthermore, no alteration in expression of mir-126 in HCV-HCC or non-viral-HCC revealed that miR-126 + AFP might be specific to HBV-HCC. To understand the physiological role of these two miRNAs in hepato-carcinogenesis, target genes related to cancer pathways (APAF1, APC2, CDKN2A, IRS1, CRKL, LIFR, EGR2) were verified. Thus, combination of circulating miR-126 + AFP is a promising noninvasive diagnostic biomarker for HBV-HCC and may be useful in the management of HCC patients.

Lu Y, Zhu M, Li W, et al.
Alpha fetoprotein plays a critical role in promoting metastasis of hepatocellular carcinoma cells.
J Cell Mol Med. 2016; 20(3):549-58 [PubMed] Free Access to Full Article Related Publications
A high level of serum alpha fetoprotein (AFP) is positively associated with human hepatocellular carcinoma (HCC) carcinogenesis and metastasis; however, the function of AFP in HCC metastasis is unknown. This study has explored the effects of AFP on regulating metastatic and invasive capacity of human HCC cells. Forty-seven clinical patients' liver samples were collected and diagnosed; HCC cells line, Bel 7402 cells (AFP-producing) and liver cancer cell line cells (non-AFP-producing) were selected to analyse the role of AFP in the metastasis of HCC cells. The results indicated that high serum concentration of AFP was positively correlated with HCC intrahepatic, lymph nodes and lung metastasis. Repressed expression of AFP significantly inhibited the capability of migration and invasion of Bel 7402 cells, expression of keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), matrix metalloproteinase 2/9 (MMP2/9) and CXC chemokine receptor 4 (CXCR4) were also down-regulated in Bel 7402 cells; migration and invasion, expression of K19, EpCAM, MMP2/9 and CXCR4 were significantly enhanced when HLE cells were transfected with AFP-expressed vector. The results demonstrated that AFP plays a critical role in promoting metastasis of HCC; AFP promoted HCC cell invasion and metastasis via up-regulating expression of metastasis-related proteins. Thus, AFP may be used as a novel therapeutic target for treating HCC patients.

Liu L, Xu HX, Wang WQ, et al.
Serum CA125 is a novel predictive marker for pancreatic cancer metastasis and correlates with the metastasis-associated burden.
Oncotarget. 2016; 7(5):5943-56 [PubMed] Free Access to Full Article Related Publications
This study evaluated potential of serum tumor markers to predict the incidence and intensity of pancreatic cancer metastasis as well as patient survival. Retrospective records from 905 patients and prospective data from 142 patients were collected from two high-volume institutions. The levels of eight serum tumor markers (CA19-9, CEA, CA242, CA72-4, CA50, CA125, CA153, and AFP) commonly used in gastroenterological cancer were analyzed in all stages of pancreatic cancer. Serum CA125 levels were the most strongly associated with pancreatic cancer metastasis and were higher in patients with metastatic disease than those without. CA125 levels increased with increasing metastasis to lymph nodes and distant organs, especially the liver. High baseline CA125 levels predicted early distant metastasis after pancreatectomy and were associated with the presence of occult metastasis before surgery. An optimal CA125 cut-off value of 18.4 U/mL was identified; patients with baseline CA125 levels of 18.4 U/mL or higher had poor surgical outcomes. In addition, high serum CA125 levels coincided with the expression of a metastasis-associated gene signature and with alterations in "driver" gene expression involved in pancreatic cancer metastasis. CA125 may therefore be a promising, noninvasive, metastasis-associated biomarker for monitoring pancreatic cancer prognosis.

Hu B, Yan X, Liu F, et al.
Downregulated Expression of PTPN9 Contributes to Human Hepatocellular Carcinoma Growth and Progression.
Pathol Oncol Res. 2016; 22(3):555-65 [PubMed] Related Publications
Human hepatocellular carcinoma (HCC) is one of the most common malignant cancers, whose molecular mechanisms is remains largely. PTPN9 has recently been reported to play a critical role in breast cancer development. However, the role of PTPN9 in human HCC remains elusive. The present study aimed at investigating the potential role of PTPN9 in HCC. Western blot and immunohistochemistry were used to examine the expression of PTPN9 protein in HCC and adjacent non-tumorous tissues in 45 patients. Furthermore, Cell Counting Kit-8, flow cytometry and RNA interference experiments were performed to analyze the role of PTPN9 in the regulation of HCC cell proliferation. We showed that the expression level of PTPN9 was significantly reduced in HCC, compared with adjacent non-tumorous tissues. PTPN9 expression was inversely associated with Tumor size (P = 0.014), serum AFP level (P = 0.004) and Ki-67 expression. Low expression of PTPN9 predicted poor survival in HCC patients. Moreover, PTPN9 interference assay that PTPN9 inhibited cell proliferation in HepG2 cells. Cell apoptosis assay revealed that, silencing of PTPN9 expression significantly reduced cell apoptosis, compared with control ShRNA treatment group. Our results suggested that PTPN9 expression was down-regulated in HCC tumor tissues, and reduced PTPN9 expression was associated with worsened overall survival in HCC patients. Depletion of PTPN9 inhibits the apoptosis and promotes the proliferation of HCC cells.

Wang K, Guo WX, Li N, et al.
Serum LncRNAs Profiles Serve as Novel Potential Biomarkers for the Diagnosis of HBV-Positive Hepatocellular Carcinoma.
PLoS One. 2015; 10(12):e0144934 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy that has a poor prognosis because there is lack of methods for early diagnosis. We aimed to utilize two serum long non-coding RNAs (lncRNAs), uc001ncr and AX800134, to diagnose hepatitis B virus (HBV)-positive HCC.
METHODS: lncRNA microarrays were utilized to measure the differential expression of lncRNAs between tumor tissues and corresponding non-tumor tissues in HBV-positive hapatocellular carcinoma. uc001ncr and AX800134 were selected as candidate lncRNAs and detected in three independent cohorts containing a total of 684 participants (healthy individuals and chronic HBV patients and HBV-positive HCC patients) who were recruited between March 2011 and December 2012. A logistic regression model was constructed using a training cohort (n = 353) and validated using an independent cohort (n = 181). The area under the receiver operating characteristic curve (AUC) was utilized to evaluate the diagnostic accuracy.
RESULTS: We determined that a panel based on the expression of uc001ncr and AX800134 accurately diagnosed HBV-positive HCC (AUC values of 0.9494 and 0.9491 for the training and validation cohorts, respectively). The diagnostic performance of the panel remained high in patients with AFP≤400 ng/ml (AUC values of 0.9371 and 0.9527 for the training and validation cohorts, respectively). The panel also diagnosed early HCC (AUC values of 0.9450 and 0.9564 for the training and validation cohorts, respectively).
CONCLUSION: Our results indicated that the serum expression of uc001ncr and AX800134 has potential as novel potential biomarker for the diagnosis of HCC, especially in patients with AFP≤400 ng/ml or early-stage disease (BCLC 0+A).

Dou CY, Fan YC, Cao CJ, et al.
Sera DNA Methylation of CDH1, DNMT3b and ESR1 Promoters as Biomarker for the Early Diagnosis of Hepatitis B Virus-Related Hepatocellular Carcinoma.
Dig Dis Sci. 2016; 61(4):1130-8 [PubMed] Related Publications
BACKGROUND: DNA methylation mainly affects tumor suppressor genes in the development of hepatocellular carcinoma (HCC). However, sera methylation of specific genes in hepatitis B virus (HBV)-related HCC remains unknown.
AIMS: The purpose of this study was to identify methylation frequencies of sera E-cadherin (CDH1), DNA methyltransferase 3b (DNMT3b) and estrogen receptor 1 (ESR1) promoter in HBV-related HCC and analyze the associated clinical significance.
METHODS: Methylation-specific PCR was used to determine the frequencies of DNA methylation for CDH1, DNMT3b and ESR1 genes in sera from 183 patients with HCC, 47 liver cirrhosis (LC), 126 chronic hepatitis B (CHB), and 50 normal controls (NCs).
RESULTS: Significantly higher frequencies of methylation of CDH1, DNMT3b and ESR1 were found in HBV-related HCC compared with LC, CHB and NCs. Nodule numbers, tumor size and the presence of liver cirrhosis were significantly associated with gene methylation status in HBV-related HCC. Moreover, HBV may have a strong and enhanced effect on the concurrent methylation of CDH1, DNMT3b and ESR1 in HBV-related HCC. More importantly, combined methylation as a biomarker displayed significantly higher diagnostic value than AFP to discriminate HCC from CHB and LC.
CONCLUSIONS: Aberrant sera DNA methylation of CDH1, DNMT3b and ESR1 gene promoters could be a biomarker in the early diagnosis of HBV-related HCC.

Qian CY, Wang KL, Fang FF, et al.
Triple-controlled oncolytic adenovirus expressing melittin to exert inhibitory efficacy on hepatocellular carcinoma.
Int J Clin Exp Pathol. 2015; 8(9):10403-11 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a highly malignant disease, and its outcome of routine therapies is poor. Comprehensive treatment including gene therapy is an important way to improve patients' prognosis and survival. In this study, we successfully constructed a triple-controlled cancer-selective oncolytic adenovirus, QG511-HA-Melittin, carrying melittin gene, in which the hybrid promoter, hypoxia-response element (HRE)-AFP promoter, was used to control viral E1a expression targeting AFP-positive cancer cells in hypoxia microenviroment, and the E1b-55 kDa gene was deleted in cancer cells with p53-deficiency. The cytological experiments found that the viral replication of QG511-HA-Melittin was increased to 12800-folds in Hep3B cells within 48 h, and 130-folds in SMMC-7721, but the virus did not replicate in L-02 cells. QG511-HA-Melittin had a strong inhibition effect on AFP-positive HCC cell proliferation, such as Hep3B and HepG2, whereas, there was low or no inhibition effect of QG511-HA-Melittin on AFP-negative cancer cells SMMC-7721 and normal cells L-02. In the in vivo experiment, compared with the blank control group, QG511-HA-Melittin can significantly inhibit the growth of HCC xenografts (P<0.05). The survival of mice in QG511-HA-Melittin group was much longer than that of the blank control group. Both in vitro and in vivo experiments manifested that QG511-HA-Melittin exerts an inhibitory effect on HCC cells, which may provide a new strategy for HCC biotherapy.

Matthai SM, Ramakrishna B
Cancer stem cells in hepatocellular carcinoma--an immunohistochemical study with histopathological association.
Indian J Med Res. 2015; 142(4):391-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & OBJECTIVES: Cancer stem cells (CSCs) may be responsible for tumour recurrence and resistance to chemotherapy in hepatocellular carcinoma (HCC). This study was carried out to evaluate the association between histological parameters and liver CSCs (LCSC) in HCC, and to compare distribution of liver CSCs in HCC associated with and without hepatitis B virus (HBV) infection.
METHODS: Seventy nine tumours (49 surgical resections from 46 patients, and 30 from autopsy) were reviewed. Immunohistochemical staining for the LCSC marker EpCAM (epithelial cell adhesion molecule), liver progenitor cell (LPC) markers CK19 (cytokeratin 19) and neural cell adhesion molecule (NCAM) were performed and were associated with histological features of tumour behaviour.
RESULTS: Thirty three tumours (41.8%) showed positive staining for EpCAM. CK19 and NCAM expression were seen in 26 (32.9%) and four (5.1%) tumours, respectively. The expression of EpCAM and CK19 was significantly associated with each other ( P<0.001). EpCAM expression was significantly associated with clinical and histological features indicating aggressive tumour behaviour, including younger age of onset, higher serum alpha foetoprotein (AFP) levels, tumour cell dedifferentiation, increased mitotic activity, and vascular invasiveness. There was no significant difference in expression of EpCAM, CK19 and NCAM between HBV positive and negative HCC.
INTERPRETATION & CONCLUSIONS: The LCSC marker EpCAM was expressed in less than half of HCC, was independent of HBV aetiology, and was strongly associated with clinical and histological features of aggressive tumour behaviour. Positive staining for CK19 suggests a possible LPC origin of the EpCAM positive HCCs.

Pan L, Yao M, Zheng W, et al.
Abnormality of Wnt3a expression as novel specific biomarker for diagnosis and differentiation of hepatocellular carcinoma.
Tumour Biol. 2016; 37(4):5561-8 [PubMed] Related Publications
The member 3a of Wingless-type MMTV integration site family (Wnt3a) as an oncogene is overexpressed in many kinds of tumors with a worse outcome. However, the mechanism and alteration of Wnt3a expression in hepatocellular carcinoma (HCC) have not been clarified. In this study, the levels of Wnt3a expression were investigated in 80 HCC tissues or sera of 186 patients with chronic liver diseases. The incidence of hepatic Wnt3a expression in HCC tissues was 96.25 % and significantly higher (χ (2) = 48.818, P < 0.001) than that in their surrounding tissues (46.25 %). The higher level (>800 ng/L) of circulating Wnt3a expression was found in 92.5 % HCC patients and significantly related (P < 0.05) to alpha-fetoprotein (AFP) level, liver cirrhosis, hepatitis B virus infection, poor differentiation, tumor node metastasis, and extra-hepatic metastasis. The level of Wnt3a expression in HCC patients was obviously higher (P < 0.001) than that in any group of cases with benign liver diseases. The diagnostic specificity or the area under the receiver operating characteristic curve was 94.34 % or 0.994 in Wnt3a and 69.81 % or 0.710 in AFP for HCC, respectively. The present data suggested that Wnt3a expression associated with tumor progression should be a novel specific biomarker for diagnosis and differentiation of HCC.

Duan Y, Wong W, Chua SC, et al.
Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression.
Int J Oncol. 2016; 48(1):358-66 [PubMed] Related Publications
While various tyrosine kinases have been associated with the pathogenesis of hepatocellular carcinoma (HCC), the identification of a dominant therapeutic target among them remains a challenge. Here, we investigated the role of Tyro3, a relatively uncharacterized member of the TAM (Tyro3, Axl and Mer) receptor family. The present study aimed to profile and identify potential association between Tyro3 expression in HCC and cancer phenotypes. RNAs obtained from 55 HCC patients were quantified for Tyro3 expression in both cancerous tissue and the adjacent normal tissue. Expression profile was correlated with clinical data. These observations were further substantiated with in vitro HCC cell culture investigations.Tyro3 was strongly upregulated (>2-fold elevation) in the tumor tissue of ~42% of the patients. It was shown that higher expression level of Tyro3 was associated with the key tumor marker AFP, and the tumor diameter and liver injury marker ALT. Subsequent cell culture models indicated high expression in various HCC cell lines, in particular Hep3B. Gene silencing of Tyro3 in Hep3B effectively reduced cell proliferation, ERK phosphorylation and cyclin D1 expression, indicating a key in maintaining the proliferative state of these cells. Notably, silencing also suppressed the transcriptional and translational expression of HCC tumor marker AFP. Overall, these data suggest that Tyro3 contributes significantly to tumor growth, aggressiveness and liver dysfunction. Inhibition of Tyro3 and its aberrant signaling in tumors with high expression could present new opportunities for HCC treatment.

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