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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:alpha-fetoprotein
HPRD
Source:NCBIAccessed: 28 February, 2015

Ontology:

What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 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.

  • Chromosome 4
  • p53 Protein
  • RTPCR
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Polymerase Chain Reaction
  • Liver Cancer
  • Liver Cirrhosis
  • Gene Expression Profiling
  • Immunohistochemistry
  • Staging
  • Liver
  • Hepatocellular Carcinoma
  • Genetic Vectors
  • Gene Expression
  • Transcription
  • Risk Factors
  • Pneumonectomy
  • Promoter Regions
  • Mice, Inbred BALB C
  • Apoptosis
  • Adolescents
  • Genetic Therapy
  • Case-Control Studies
  • Down-Regulation
  • Ploidies
  • Cancer DNA
  • Neoplasm Recurrence, Local
  • Cancer RNA
  • Molecular Sequence Data
  • Transfection
  • beta Catenin
  • Adenoviridae
  • Neoplasm Proteins
  • Hep G2 Cells
  • Tumor Antigens
  • Survival Rate
  • Base Sequence
  • DNA Methylation
  • Cell Proliferation
  • AFP
Tag cloud generated 28 February, 2015 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)

EI-Emshaty HM, Gadelhak SA, Abdelaziz MM, et al.
Serum P53 Abs in HCC patients with viral hepatitis - type C.
Hepatogastroenterology. 2014; 61(134):1688-95 [PubMed] Related Publications
BACKGROUND/AIMS: P53 gene mutations have a higher malignant potential and often leads to the production of p53 Abs. This study was conducted to evaluate the clinical implications of p53Abs in HCV-related HCC and its diagnostic capacity as a new biomarker in HCC.
METHODOLOGY: 83 patients with HCV-chronic liver disease (25 with LC and 58 with HCC) were enrolled in this study. Ten healthy individuals (HI) served as control group. The studied group was subjected to clinical examination, imaging radiology, laboratory investigation and liver biopsy. Serum p53 Abs was assessed by (ELISA).
RESULTS: Serum p53 Abs in HCC (0.5567±0.227) was significantly elevated (p<0.0001) than LC (0.252±0.0099) and HI (0.214±0.068) (p=0.001). Serum P53 Abs was significantly (p=0.01) increased with the progression of child score but there was no significant difference with regard to age, sex, tumor size or serum liver profile. However, serum p53 Abs showed no significant positive correlation with AFP in HCV-related HCC (r=0.09, p value= 0.6) but serum p53 Abs in combination with AFP showed higher diagnostic sensitivity (82.2%) of HCC than either alone.
CONCLUSIONS: P53 Abs could be regarded as a specific biomarker for cancer process and its use in combination with AFP may increase the diagnostic sensitivity of HCC.

Liu Y, Wang M, Feng H, Li A
Comprehensive study of tumour single nucleotide polymorphism array data reveals significant driver aberrations and disrupted signalling pathways in human hepatocellular cancer.
IET Syst Biol. 2014; 8(2):24-32 [PubMed] Related Publications
The authors describe an integrated method for analysing cancer driver aberrations and disrupted pathways by using tumour single nucleotide polymorphism (SNP) arrays. The authors new method adopts a novel statistical model to explicitly quantify the SNP signals, and therefore infers the genomic aberrations, including copy number alteration and loss of heterozygosity. Examination on the dilution series dataset shows that this method can correctly identify the genomic aberrations even with the existence of severe normal cell contamination in tumour sample. Furthermore, with the results of the aberration identification obtained from multiple tumour samples, a permutation-based approach is proposed for identifying the statistically significant driver aberrations, which are further incorporated with the known signalling pathways for pathway enrichment analysis. By applying the approach to 286 hepatocellular tumour samples, they successfully uncover numerous driver aberration regions across the cancer genome, for example, chromosomes 4p and 5q, which harbour many known hepatocellular cancer related genes such as alpha-fetoprotein (AFP) and ectodermal-neural cortex (ENC1). In addition, they identify nine disrupted pathways that are highly enriched by the driver aberrations, including the systemic lupus erythematosus pathway, the vascular endothelial growth factor (VEGF) signalling pathway and so on. These results support the feasibility and the utility of the proposed method on the characterisation of the cancer genome and the downstream analysis of the driver aberrations and the disrupted signalling pathways.

Zhang S, Liang X, Zheng X, et al.
Glo1 genetic amplification as a potential therapeutic target in hepatocellular carcinoma.
Int J Clin Exp Pathol. 2014; 7(5):2079-90 [PubMed] Free Access to Full Article Related Publications
Glyoxalase 1 (Glo1) gene aberrations is associated with tumorigenesis and progression in numerous cancers. In this study, we explored the role of Glo1 genetic amplification and expression in Chinese patients with hepatocellular carcinoma (HCC), and Glo1 genetic amplification as potential therapeutic target for HCC. We used fluorescence in situ hybridization (FISH) analysis and qRT-PCR to examine Glo1 genetic aberrations and Glo1 mRNA expression in paired tumor samples obtained from HCC patients. Glo1 genetic amplification was identified in a subset of HCC patient (6%, 3/50), and up-regulation of Glo1 expression was found in 48% (24/50) of tumor tissues compared with adjacent non-tumorous tissues. Statistic analysis showed that Glo1-upregulation significantly correlated with high serum level of alpha-fetoprotein (AFP). Interfering Glo1 expression with shRNA knocking-down led to significant inhibition of cell growth and induced apoptosis in primarily cultured HCC cells carrying genetic amplified Glo1 gene, while no inhibitory effects on cell proliferation were observed in HCC cells with normal copies of Glo1 gene. Glo1 knockdown also inhibited tumor growth and induced apoptosis in xenograft tumors established from primarily cultured HCC cells with Glo1 gene amplification. In addition, Glo1 knocking-down with shRNA interfering caused cellular accumulation of methylglyoxal, a Glo1 cytotoxic substrate. Our data suggested Glo1 pathway activation is required for cell proliferation and cell survival of HCC cells carrying Glo1 genetic amplification. Intervention of Glo1 activation could be a potential therapeutic option for patients with HCC carrying Glo1 gene amplification.

Kurayoshi K, Ozono E, Iwanaga R, et al.
Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs.
Biochem Biophys Res Commun. 2014; 450(1):240-6 [PubMed] Related Publications
In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicide gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter is activated by E2F only in cancer cells and therefore may be more cancer cell-specific than E2F1 promoter to drive gene expression. We show here that the ARF promoter has lower activity in normal growing fibroblasts and shows higher cancer cell-specificity compared to the E2F1 promoter. We also demonstrate that adenovirus expressing HSV-TK under the control of the ARF promoter shows lower cytotoxicity than that of the E2F1 promoter, in normal growing fibroblasts but has equivalent cytotoxicity in cancer cell lines. These results suggest that the ARF promoter, which is specifically activated by deregulated E2F activity, is an excellent candidate to drive therapeutic cytotoxic gene expression, specifically in cancer cells.

Hu GS, Li YQ, Yang YM, et al.
High expression of Golgi phosphoprotein-3 is associated with poor survival in patients with hepatocellular carcinoma.
Tumour Biol. 2014; 35(9):8625-32 [PubMed] Related Publications
Golgi phosphoprotein 3 (GOLPH3) is recently demonstrated to function as an oncogene involved in the development and progression of cancers. However, little is known about GOLPH3 expression and its clinical significance in hepatocellular carcinoma (HCC). The levels of GOLPH3 messenger RNA (mRNA) and protein in HCC cell lines and fresh tissues were determined by quantitative RT-PCR and western blotting. Additionally, the protein expression of GOLPH3 was detected in 167 paraffin-embedded HCC samples by immunohistochemistry. GOLPH3 mRNA and protein was overexpressed in HCC cell lines and tissues than the immortalized normal hepatocyte cell line LO2 and the adjacent nontumorous live tissues, respectively. High GOLPH3 expression was positively correlated with high serum AFP level (P = 0.015) and more tumor recurrence or metastasis (P = 0.010). In addition, HCC patients with high GOLPH3 expression had poorer overall survival (hazard ratio (HR), 1.87; 95 % confidence interval (CI), 1.19-2.94; P = 0.006) and poorer disease-free survival (HR, 1.90; 95 % CI, 1.21-2.98; P = 0.005) than those with low GOLPH3 expression. The cumulative 5-year survival rate was only 35.19 % (95 % CI, 26.18-44.20 %) in the high GOLPH3 expression group, whereas it was 55.93 % (95 % CI, 43.26-68.60 %) in the low GOLPH3 expression group. Furthermore, multivariate Cox regression analysis demonstrated that the expression of GOLPH3, tumor size, and tumor multiplicity were independent prognostic predictors for HCC patients. GOLPH3 was overexpressed in HCC at both the mRNA and protein levels, and high expression of GOLPH3 could be served as a novel and potential prognostic biomarker for HCC patients.

Han SX, Bai E, Jin GH, et al.
Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma.
J Immunol Res. 2014; 2014:261365 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Yes-associated protein (YAP) and PDZ-binding motif (TAZ) are two important effectors of Hippo pathway controlling the balance of organ size and carcinogenesis. Amphiregulin (AREG) is a member of the epidermal growth factor family, a direct target gene of YAP and TAZ. The role of these proteins in hepatocellular carcinoma (HCC) is unclear.
METHODS: The expression of YAP, TAZ, and AREG in HCC was analyzed by immunohistochemical staining. The level of secreted serum AREG was also assayed by enzyme-linked immunosorbent (ELISA) assay.
RESULTS: YAP, TAZ, and AREG were expressed in 69.2% (27/39), 66.7% (26/39), and 61.5% (24/39) of HCC patients. The expression of YAP was significantly correlated with Edmondson stage (P>0.05), serum AFP level (P>0.05), and HCC prognosis (P>0.05). AREG expression was also significantly correlated with Edmondson stage (P>0.05) and serum AFP level (P>0.05). In addition, the expression of serum AREG was higher than serum AFP in HCC patients. Further multivariate analysis showed that YAP expression was an independent prognostic factor that significantly affected the overall survival of HCC patients.
CONCLUSIONS: YAP maybe an independent prognostic indicator for HCC patients and serum AREG may be a serological biomarker of HCC.

Gao Y, Li Z, Guo X, et al.
DLX4 as a prognostic marker for hepatocellular carcinoma.
Neoplasma. 2014; 61(3):318-23 [PubMed] Related Publications
Distal-less homeobox gene 4 (DLX4) has been shown to play a role in carcinogenesis. The value of DLX4 in hepatocellular carcinoma (HCC) has not been fully investigated. Here, we sought to quantify the expression of DLX4 in association with the clinicopathological features and prognosis in hepatocellular carcinoma (HCC). We examined DLX4 expression in 45 HCC tissues and matched adjacent noncancerous tissues by quantitative RT-PCR (qRT-PCR) and Western blotting. Furthermore, 226 HCC samples were analyzed for DLX4 expression by immunohistochemistry. The expression of DLX4 was significantly elevated in HCC tissues in comparison with that in adjacent non-cancerous tissues (P<0.01). The high expression of DLX4 in HCC was significantly correlated with tumor size, histopathologic classifications, and serum alpha-fetoprotein (AFP). Kaplan-Meier survival analysis revealed that increased expression of DLX4 correlated with poor clinical outcomes of HCC patients (P<0.01). Subsequent multivariate analysis showed that DLX4 expression was an independent prognostic biomarker for overall survival of HCC patients. These results suggest that high expression of DLX4 predicts HCC prognosis, and DLX4 may be potentially an important therapeutic target for HCC.

Tsang FH, Au V, Lu WJ, et al.
Prognostic marker microRNA-125b inhibits tumorigenic properties of hepatocellular carcinoma cells via suppressing tumorigenic molecule eIF5A2.
Dig Dis Sci. 2014; 59(10):2477-87 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) belong to a group of small non-coding RNA with differential expression in tumors, including hepatocellular carcinoma (HCC).
AIM: This study investigates the involvement of miR-125b in HCC.
METHODS: Clinical analysis of miR-125b was performed using data derived from miRNA profiling and qPCR. Phenotypic changes of liver cell lines were examined after ectopic miR-125b expression. Lastly, bioinformatics analysis coupled with luciferase reporter assay was used to reveal the cellular target of miR-125b.
RESULTS: A down-regulation of miR-125b was found in HCC tumors and cultured cells. Patients having tumors with ≥twofold reduction in miR-125b compared to adjacent non-tumor tissues contributed to 23 out of 49 HCC cases (46.9 %), while this down-regulation was usually found in patients with tumor venous infiltration and recurrence. miR-125b expression was also negatively correlated with increased serum AFP level and poor overall survival of patients. Ectopic expression of miR-125b led to alleviated tumor phenotypes of HCC cells. Among the 110 bioinformatically predicated candidates, 31 of them negatively correlated with miR-125b in HCC tumors for which one of them named eukaryotic translation initiation factor 5A2 (eIF5A2), known also as a liver oncofetal molecule, was validated to be a direct target of miR-125b in HCC.
CONCLUSIONS: This study has evidenced for the negative correlation of tumor miR-125b expression with poor prognosis of HCC patients. Expression of miR-125b can reverse the tumorigenic properties of cultured HCC cells via suppressing the tumorigenic molecule eIF5A2, thus postulating restoration of miR-125b level as a way to counteract liver tumorigenesis.

Fatima S, Luk JM, Poon RT, Lee NP
Dysregulated expression of dickkopfs for potential detection of hepatocellular carcinoma.
Expert Rev Mol Diagn. 2014; 14(5):535-48 [PubMed] Related Publications
The prognosis for hepatocellular carcinoma (HCC) remains dismal due to the lack of diagnostic markers for early detection. This review will discuss the clinical potential of the dickkopf (DKK) family members as diagnostic and/or prognostic markers for HCC. In comparison to serum α-fetoprotein (AFP) level, which remains the gold standard for HCC diagnosis, high serum DKK1 levels have higher diagnostic value for HCC, especially for AFP-negative HCC, and can distinguish HCC from non-malignant chronic liver diseases. Additionally, the combination of serum DKK1 and AFP levels enhances diagnostic accuracy for HCC compared to serum DKK1 or AFP levels alone. Although DKK1 offers potential for its use in HCC diagnosis this review will discuss the challenges facing DKK1 and also shed some light on recent developments on the remaining DKK family members: DKK2, DKK3 and DKK4.

Parpart S, Roessler S, Dong F, et al.
Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome.
Hepatology. 2014; 60(3):872-83 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
UNLABELLED: Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P<0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly (P<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P<0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP- HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR-29a expression and induces DNMT3A expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP- HCC cells in nude mice.
CONCLUSION: Tumor biology differs considerably between AFP+ HCC and AFP- HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC.

Kole MJ, Fridley JS, Jea A, Bollo RJ
Currarino syndrome and spinal dysraphism.
J Neurosurg Pediatr. 2014; 13(6):685-9 [PubMed] Related Publications
Currarino syndrome is a rare constellation of congenital anomalies characterized by the triad of sacral dysgenesis, presacral mass, and anorectal malformation. It is frequently associated with other congenital anomalies, often including occult spinal dysraphism. Mutations in the MNX1 gene are identified in the majority of cases. The authors report a rare case of Currarino syndrome in an infant with tethered cord syndrome and a dorsal lipomyelomeningocele continuous with a presacral intradural spinal lipoma, in addition to an imperforate anus and a scimitar sacrum. They review the literature to highlight patterns of occult spinal dysraphism in patients with Currarino syndrome and their relationship to tethered cord syndrome. Approximately 60% of the patients with Currarino syndrome reported in the literature have an occult spinal dysraphism. Published studies suggest that the risk of tethered cord syndrome may be higher among patients with a lipoma and lower among those with a teratoma or anterior meningocele.

Hu BG, Liu LP, Chen GG, et al.
Therapeutic efficacy of improved α-fetoprotein promoter-mediated tBid delivered by folate-PEI600-cyclodextrin nanopolymer vector in hepatocellular carcinoma.
Exp Cell Res. 2014; 324(2):183-91 [PubMed] Related Publications
SNPs in human AFP promoter are associated with serum AFP levels in hepatocellular carcinoma (HCC), suggesting that AFP promoter variants may generate better transcriptional activities while retaining high specificity to AFP-producing cells. We sequenced human AFP promoters, cloned 15 different genotype promoters and tested their reporter activities in AFP-producing and non-producing cells. Among various AFP variant fragments tested, EA4D exhibited the highest reporter activity and thus was selected for the further study. EA4D was fused with tBid and coupled with nano-particle vector (H1) to form pGL3-EA4D-tBid/H1. pGL3-EA4D-tBid/H1 could express a high level of tBid while retain the specificity to AFP-producing cells. In a HCC tumor model, application of pGL3-EA4D-tBid/H1 significantly inhibited the growth of AFP-producing-implanted tumors with minimal side-effects, but had no effect on non-AFP-producing tumors. Furthermore, pGL3-EA4D-tBid/H1 could significantly sensitize HCC cells to sorafenib, an approved anti-HCC agent. Collectively, pGL3-EA4D-tBid/H1, a construct with the AFP promoter EA4D and the novel H1 delivery system, can specifically target and effectively suppress the AFP-producing HCC. This new therapeutic tool shows little toxicity in vitro and in vivo and it should thus be safe for further clinical tests.

Kim SW, Yang HG, Kang MC, et al.
KIAA1114, a full-length protein encoded by the trophinin gene, is a novel surface marker for isolating tumor-initiating cells of multiple hepatocellular carcinoma subtypes.
Oncotarget. 2014; 5(5):1226-40 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Identification of novel biomarkers for tumor-initiating cells (TICs) is of critical importance for developing diagnostic and therapeutic strategies against cancers. Here we identified the role of KIAA1114, a full-length translational product of the trophinin gene, as a distinctive marker for TICs in human liver cancer by developing a DNA vaccine-induced monoclonal antibody targeting the putative extracellular domain of KIAA1114. Compared with other established markers of liver TICs, KIAA1114 was unique in that its expression was detected in both alpha fetoprotein (AFP)-positive and AFP-negative hepatocellular carcinoma (HCC) cell lines with the expression levels of KIAA1114 being positively correlated to their tumorigenic potentials. Notably, KIAA1114 expression was strongly detected in primary hepatic tumor, but neither in the adjacent non-tumorous tissue from the same patient nor normal liver tissue. KIAA1114high cells isolated from HCC cell lines displayed TIC-like features with superior functional and phenotypic traits compared to their KIAA1114low counterparts, including tumorigenic abilities in xenotransplantation model, in vitro colony- and spheroid-forming capabilities, expression of stemness-associated genes, and migratory capacity. Our findings not only address the value of a novel antigen, KIAA1114, as a potential diagnostic factor of human liver cancer, but also as an independent biomarker for identifying TIC populations that could be broadly applied to the heterogeneous HCC subtypes.

Kuo CC, Lin CY, Shih YL, et al.
Frequent methylation of HOXA9 gene in tumor tissues and plasma samples from human hepatocellular carcinomas.
Clin Chem Lab Med. 2014; 52(8):1235-45 [PubMed] Related Publications
BACKGROUND: Aberrant DNA methylation is associated with the development of hepatocellular carcinoma (HCC), suggesting that gene methylation could be a potential biomarker for detection of HCC. The aim of this study is to identify potential biomarkers in HCC.
METHODS: We used the Infinium methylation array and a DNA-pooling strategy to analyze the genome-wide methylation profile in HCC. Quantitative methylation-specific PCR (Q-MSP) was used to validate homeobox A9 (HOXA9) methylation in 29 normal controls, 100 HCC samples and adjacent non-tumor tissues and in 74 plasma samples, including 40 patients with HCC.
RESULTS: Ten genes (HOXA9, NEUROG1, TNFRSF10C, IRAK3, GFPT2, ZNF177, DPYSL4, ELOVL4, FSD1, and CACNA1G) showed differences in methylation between controls and HCCs. Of these, HOXA9 was significantly hypermethylated in HCCs (76.7%; 23/30) compared with controls (3.4%; 1/29). In addition, combination analysis of two- and three-gene sets for HCC detection showed greater sensitivity (90%-96.7%) and comparable specificity (93.1%-96.6%) to each individual gene (33.3%-76.7% and 55.2%-100.0%). HOXA9 methylation was further validated by Q-MSP in two independent set of clinical samples including 100 HCC and paired non-tumor tissues. Further, HOXA9 methylation could be detected in plasma from HCC patients (n=40) but not in normal plasma (n=34) (p<0.0005). Combined testing (either parameter positive) for α-fetoprotein (AFP, a plasma protein biomarker) and HOXA9 methylation showed greater sensitivity (94.6%) for detection of HCC than AFP alone (75.7%).
CONCLUSIONS: These data suggest that methylation of HOXA9 could be a helpful biomarker to assist in HCC detection.

Nojiri S, Joh T
Albumin suppresses human hepatocellular carcinoma proliferation and the cell cycle.
Int J Mol Sci. 2014; 15(3):5163-74 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC) is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of HCC has not yet been elucidated, so we investigated the effect of serum albumin on HCC cell proliferation. Hep3B was cultured in MEM with no serum or containing 5 g/dL human albumin. As control samples, Prionex was added to generate the same osmotic pressure as albumin. After 24-h incubation, the expressions of α-fetoprotein (AFP), p53, p21, and p57 were evaluated with real-time PCR using total RNA extracted from the liver. Protein expressions and the phosphorylation of Rb (retinoblastoma) were determined by Western blot analysis using total protein extracted from the liver. For flow cytometric analysis of the cell cycle, FACS analysis was performed. The percentages of cell cycle distribution were evaluated by PI staining, and all samples were analyzed employing FACScalibur (BD) with appropriate software (ModFit LT; BD). The cell proliferation assay was performed by counting cells with using a Scepter handy automated cell counter (Millipore). The mRNA levels of AFP relative to Alb(-): Alb(-), Alb(+), and Prionex, were 1, 0.7 ± 0.2 (p < 0.001 for Alb(-)), and 1 ± 0.3, respectively. The mRNA levels of p21 were 1, 1.58 ± 0.4 (p = 0.007 for Alb(-) and p = 0.004 for Prionex), and 0.8 ± 0.2, respectively. The mRNA levels of p57 were 1, 4.4 ± 1.4 (p = 0.002 for Alb(-) and Prionex), and 1.0 ± 0.1, respectively. The protein expression levels of Rb were similar in all culture media. The phosphorylation of P807/811 and P780 of Rb protein was reduced in Alb(+). More cells in the G0/G1 phase and fewer cells in S and G2/M phases were obtained in Alb(+) than in Alb(-) (G0/G1: 60.9%, 67.7%, 61.5%; G2/M: 16.5%, 13.1%, 15.6%; S: 22.6%, 19.2%, 23.0%, Alb(-), Alb(+), Prionex, respectively). The same results were obtained in HepG2. Cell proliferation was inhibited in 5 g/dL albumin medium in both HepG2 cells and Hep3B cells in 24 h culture by counting cell numbers. The presence of albumin in serum reduces the phosphorylation of Rb proteins and enhances the expression of p21 and p57, following an increase in the G0/G1 cell population, and suppresses cell proliferation. These results suggest that albumin itself suppresses the proliferation of hepatocellular carcinoma.

Rashad NM, El-Shal AS, Abd Elbary EH, et al.
Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma.
Cytokine. 2014; 68(1):50-8 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population.
MATERIALS AND METHODS: Four hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA.
RESULTS: Serum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08-0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child-Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients.
CONCLUSION: IGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.

Hu S, Wu X, Zhou B, et al.
IMP3 combined with CD44s, a novel predictor for prognosis of patients with hepatocellular carcinoma.
J Cancer Res Clin Oncol. 2014; 140(6):883-93 [PubMed] Related Publications
PURPOSE: Insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) is reported to be re-expressed in malignant tumors and can regulate the expression of multiple genes related to tumor invasion. CD44 standard isoform (CD44s) has been reported to play an important role in facilitating tumor invasion. In this text, we investigate the regulatory function of IMP3 on CD44s and the role of IMP3 and CD44s in predicting the outcomes of patients with hepatocellular carcinoma.
METHODS: IMP3 and CD44s were measured in hepatocellular carcinoma (HCC) tissues by immunohistochemical assay, and survival analysis was conducted among 128 patients. Moreover, we studied the effect of IMP3 on the expression of CD44s and the biological functions of tumor cells in HCC cell lines.
RESULTS: Our results showed that the expression of IMP3 was significantly correlated with CD44s expression (r = 0.505, P < 0.001), and both of them correlated with high AFP level, advanced tumor stage and grade, portal vein tumor thrombus, and early tumor recurrence or metastasis. The results of survival analysis exhibited that the 1-, 3-, 5-year disease-free and overall survival rates significantly reduced in IMP3- and CD44s-positive patients, and IMP3 combined with CD44s was an independent prognostic risk factor for HCC. In vitro assay, our results showed that IMP3 promoted HepG2 and MHCC97H cells invading and migrating via regulating CD44s expression.
CONCLUSIONS: Our findings suggest that IMP3 facilitates HCC aggressiveness through regulating CD44s expression, and IMP3 combined with CD44s can be as a new predictor for unfavorable prognosis in HCC patients.

Yang Y, Fan YC, Gao S, et al.
Methylated cysteine dioxygenase-1 gene promoter in the serum is a potential biomarker for hepatitis B virus-related hepatocellular carcinoma.
Tohoku J Exp Med. 2014; 232(3):187-94 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Epigenetic analysis has attracted increasing attention in the molecular diagnosis of HCC. Cysteine dioxygenase 1 (CDO1) is a key enzyme in the taurine biosynthetic pathway and converts cysteine to cysteine sulfinate. The CDO1 gene is a tumor suppressor gene and is usually silenced by the methylation of its promoter in carcinogenesis. In this study, we evaluated whether the methylation status of CDO1 gene promoter is of diagnostic value for hepatitis B virus (HBV)-related HCC. The CDO1 promoter methylation status was determined in serum samples using methylation-specific polymerase chain reaction (MSP) in a cohort of 123 patients with HBV-related HCC, 28 with liver cirrhosis (LC), 29 with chronic hepatitis B (CHB) and 20 healthy controls. The frequency of the CDO1 promoter methylation in HBV-related HCC (42.3%) was significantly higher than that in LC (14.3%), CHB (6.9%) and healthy controls (0%) (P = 0.006; P < 0.0001; P < 0.0001; respectively). Furthermore, in HCC patients, the frequency of CDO1 promoter methylation was higher in advanced stages (III-IV) (53%) than the early stages (I-II) (20%) (P = 0.001). Evaluation of the CDO1 promoter methylation status in serum, in combination with AFP (> 20 ng/ml), significantly improved the diagnostic value, with sensitivity and specificity of 82.9% and 75.4%, respectively in distinguishing HCC from LC and CHB. In conclusion, methylation status of serum CDO1 gene promoter may be helpful in the diagnosis of HCC and the estimation of the HCC stages.

Zhang F, Fan YC, Mu NN, et al.
Exportin 4 gene expression and DNA promoter methylation status in chronic hepatitis B virus infection.
J Viral Hepat. 2014; 21(4):241-50 [PubMed] Related Publications
Exportin 4 (XPO4) is a novel identified candidate tumour-suppressor gene involved in the pathogenesis of hepatocellular carcinoma (HCC). This study was aimed to determine the clinical features of XPO4 mRNA expression and promoter methylation status in peripheral blood mononuclear cells (PBMCs) of patients with chronic hepatitis B virus (HBV) infection. PBMCs were isolated from 44 HCC, 38 liver cirrhosis (LC), 34 chronic hepatitis B (CHB) patients and 17 healthy controls (HCs). The mRNA level and promoter methylation status of XPO4 were determined by quantitative real-time RT-PCR and methylation-specific PCR, respectively. XPO4 mRNA level of HCC patients was significantly lower compared with LC and CHB patients as well as HCs (all P < 0.01, respectively), and significant differences of the XPO4 mRNA level were found in LC and CHB group than in HCs (LC vs HCs, P < 0.01; CHB vs HCs, P < 0.05). Methylation rate of XPO4 promoter was significantly increased in patients with HCC than in patients with CHB and HCs (both P < 0.05). DNA methylation pattern was responsible for the suppression of XPO4 transcription in the progression of HBV infection (P = 0.000). Furthermore, AFP level was significantly higher in HCC patients with XPO4 methylation than in those without methylation ((8702 ± 15635) μm vs (1052 ± 5370) μm, P < 0.05). In conclusion, transcription of XPO4 gene was gradually decreased and methylation rate of XPO4 promoter was increased with the progression of HBV infection. Methylation status of XPO4 in PBMCs tended to be a noninvasive biomarker to predict HCC and the progression of HBV infection.

Xiao J, Ding Y, Huang J, et al.
The association of HMGB1 gene with the prognosis of HCC.
PLoS One. 2014; 9(2):e89097 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
High-mobility group box 1 protein (HMGB1) is an evolutionarily ancient and critical regulator of cell death and survival. HMGB1 is a chromatin-associated nuclear protein molecule that triggers extracellular damage. The expression of HMGB1 has been reported in many types of cancers, but the role of HMGB1 in hepato cellular carcinoma (HCC) is unknown.The aim of this study was to analyze the roles of HMGB1 in HCC progression using HCC clinical samples. We also investigated the clinical outcomes of HCC samples with a special focus on HMBG1 expression. In an immunohistochemical study conducted on 208 cases of HCC, HMGB1 had high expression in 134 cases(64.4%).The HMGB1 expression level did not correlate with any clinicopathological parameters, except alpha fetoprotein (AFP) (p = 0.041) and CLIP stage (p = 0.007). However, survival analysis showed that the group with HMBG1 overexpression had a significantly shorter overall survival time than the group with a down-regulated expression of HMBG1 (HR = 0.568, CI (0.398, 0.811), p = 0.002). Multivariate analysis showed that HMGB1 expression was a significant and independent prognostic parameter (HR = 0.562, CI (0.388, 0.815), p = 0.002) for HCC patients. The ability of proliferation, migration and invasion of HCC cells was suppressed with the disruption of endogenous HMGB1 using small interfering RNAs. On the other hand, the ability of proliferation, migration and invasion of HCC cells was strengthened when the expression endogenous HMGB1 was enhanced using HMGB1 DNA. HMGB1 expression may be a novel and independent predictor for the prognosis of HCC patients. The overexpression of HMGB1 in HCC could be a novel, effective, and supplementary biomarker for HCC, since it plays a vital role in the progression of HCC.

Wray CJ, Ko TC, Tan FK
Secondary use of existing public microarray data to predict outcome for hepatocellular carcinoma.
J Surg Res. 2014; 188(1):137-42 [PubMed] Related Publications
BACKGROUND: Since 1990, numerous public repositories of microarray data have been created to store vast genomic data sets. Our hypothesis is that a secondary analysis of an available hepatocellular carcinoma (HCC) public data set could generate new findings and additional hypotheses.
METHODS: The Gene Expression Omnibus at the National Center for Biotechnology Information was queried for available data sets specific for 'HCC' and 'clinical data.' Genes that passed filtering and normalization criteria were analyzed using the class comparison and prediction functions in BRB-ArrayTools. Ingenuity pathway analysis software was used to identify potential gene networks up- or down-regulated.
RESULTS: The file GDS274, which measured gene expression in primary HCC lesions with or without hepatic metastases from a cohort of Chinese patients, was identified as an appropriate data set and was imported into BRB-ArrayTools. 9984 genes passed filtering criteria. Clinical data demonstrated alpha fetoprotein (AFP) >100 ng/mL predictive of worse survival (HR 5.87, 95% confidence interval: 1.11-31.0). A class comparison between patients with an AFP >100 and those with AFP <100 demonstrated 92 genes to be differentially expressed. Ingenuity pathway analyses demonstrated the top networks associated with the observed gene expression.
CONCLUSIONS: Using available HCC microarray data, we identified genes differentially expressed based on AFP >100. Canonical pathway analysis demonstrated functional gene pathways and associated upstream regulators. This study maximizes the use of publicly available data by generating new findings. Secondary analyses of these data sets should be considered by investigators before embarking on new genomic experiments.

Fan M, Liu Y, Xia F, et al.
Increased expression of EphA2 and E-N cadherin switch in primary hepatocellular carcinoma.
Tumori. 2013 Nov-Dec; 99(6):689-96 [PubMed] Related Publications
AIM: To investigate the expression and clinical significance of ephrin type-A receptor 2 and epithelial-mesenchymal transition-related proteins in primary hepatocellular carcinoma.
METHODS: Tissues from 52 primary hepatocellular carcinomas and 12 human normal liver tissues were detected for expression of ephrin type-A receptor 2, E-cadherin, and N-cadherin by immunochemistry. Cinicopathological features of hepatocellular carcinoma and tumor recurrence after operation were studied for the association with these molecular expressions and E-N cadherin switch.
RESULTS: Increased expressions of ephrin type-A receptor 2 and N-cadherin and reduced expression of E-cadherin were significantly detected in hepatocellular carcinoma compared with normal liver tissues. Univariate analysis showed that there were close associations between unfavorable clinicopathological features and expressions of ephrin type-A receptor 2, E-cadherin, N-cadherin, and E-N cadherin switch. Ephrin type-A receptor 2 and E-cadherin expressions were confirmed as independent prognostic factors when corrected with age, gender, AFP, HBsAg, liver cirrhosis, tumor size, nodules, capsule, portal vein invasion, cell differentiation, and TNM stage.
CONCLUSIONS: The overexpression of ephrin type-A receptor 2 protein is correlated with the number of tumors, capsular integrity, portal vein cancer thrombus and clinical stages. Epithelial-mesenchymal transition regulated by ephrin type-A receptor 2 is involved in the aggressive clinicopathological features and prognosis, suggesting that the receptor may play an important role in the progression and metastasis of hepatocellular carcinoma.

Xu M, Xie F, Qian G, et al.
Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma.
BMC Cancer. 2014; 14:65 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: The role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated.
METHODS: In this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated.
RESULTS: Peritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis.
CONCLUSIONS: These results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection.

Chen J, Liu WB, Jia WD, et al.
Embryonic morphogen nodal is associated with progression and poor prognosis of hepatocellular carcinoma.
PLoS One. 2014; 9(1):e85840 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Nodal, a TGF-β-related embryonic morphogen, is involved in multiple biologic processes. However, the expression of Nodal in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis, epithelial-mesenchymal transition, and prognosis is unclear.
METHODS: We used real-time PCR and Western blotting to investigate Nodal expression in 6 HCC cell lines and 1 normal liver cell line, 16 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine Nodal expression in HCC and corresponding paracarcinomatous tissues from 96 patients. CD34 and Vimentin were only examined in HCC tissues of patients mentioned above. Nodal gene was silenced by shRNA in MHCC97H and HCCLM3 cell lines, and cell migration and invasion were detected. Statistical analyses were applied to evaluate the prognostic value and associations of Nodal expression with clinical parameters.
RESULTS: Nodal expression was detected in HCC cell lines with high metastatic potential alone. Nodal expression is up-regulated in HCC tissues compared with paracarcinomatous and normal liver tissues. Nodal protein was expressed in 70 of the 96 (72.9%) HCC tumors, and was associated with vascular invasion (P = 0.000), status of metastasis (P = 0.004), AFP (P = 0.049), ICGR15 (indocyanine green retention rate at 15 min) (P = 0.010) and tumor size (P = 0.000). High Nodal expression was positively correlated with high MVD (microvessal density) (P = 0.006), but not with Vimentin expression (P = 0.053). Significantly fewer migrated and invaded cells were seen in shRNA group compared with blank group and negative control group (P<0.05). High Nodal expression was found to be an independent factor for predicting overall survival of HCC.
CONCLUSIONS: Our study demonstrated that Nodal expression is associated with aggressive characteristics of HCC. Its aberrant expression may be a predictive factor of unfavorable prognosis for HCC after surgery.

Han LY, Fan YC, Mu NN, et al.
Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a potential biomarker for hepatitis B Virus associated hepatocellular carcinoma.
Int J Med Sci. 2014; 11(2):164-71 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients.
METHODS: The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP).
RESULTS: Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients ≥60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50.
CONCLUSIONS: Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients.

Chen S, Chen J, Xi W, et al.
Clinical therapeutic effect and biological monitoring of p53 gene in advanced hepatocellular carcinoma.
Am J Clin Oncol. 2014; 37(1):24-9 [PubMed] Related Publications
OBJECTIVE: To investigate the therapeutic effect and biological changes of hepatic arterial infusion of p53 gene by the percutaneous port catheter system on advanced hepatocellular carcinoma (HCC) through a prospective randomized trial.
METHODS: A total of 48 patients with advanced HCC between May 2005 and January 2009 were divided into the treatment group (30) and the control group (18). The port catheter system was implanted through the right external iliac artery approach in all the cases; the target artery was determined according to the manifestation of the angiograph. The patients in the treatment group were given arterial infusion of p53 gene (Gendicine, Shenzhen Sibiono GeneTech Co, Ltd) with Gendicine (10vp) combined with hydroxycamptothecin (20 mg), once a week, for a course continuously for 3 weeks. The arterial infusion with hydroxycamptothecin (20 mg) was given to the patients in the control group. Pretreatment/posttreatment a fetus protein and Karnofsky Performance Status values, change of tumor according to Response Evaluation Criteria in Solid Tumors (RECIST), and the survival time were analyzed. Pretreatment/posttreatment expression of mutant p53 gene and spontaneous micronucleus formation in the peripheral blood were evaluated by flow cytometry and micronucleus test in vivo.
RESULTS: The patients in the treatment group received 1 to 8 courses of treatment, in which the differences between pretreatment/posttreatment AFP and KPS values were significant (P < 0.05), whereas there was no significant difference (P > 0.05) between pretreatment/posttreatment AFP and KPS values within the control group. After 1 month, the survival rates of the treatment and control groups (96.6% and 94.4%, respectively) and changes in the tumor evaluated according to RECIST were significantly different (P < 0.05) between the 2 groups. After 3 months, the survival rates of the treatment and control groups (83.3% and 55.6%, respectively) and changes in the tumor were also significantly different between the 2 groups (P < 0.05). After 6 months, the survival rates (50% and 11%, respectively) and changes in the tumor were significantly different between the 2 groups (P < 0.05). After 9 months, the survival rates (23.3% and 0%, respectively) and changes in the tumor were significantly different between the 2 groups (P < 0.05). Finally, after 12 months, the survival rates (6.67% and 0%, respectively) and changes in the tumor were significantly different between the 2 groups (P < 0.05). The difference between the pretreatment and posttreatment mean rates of p53 expression in patients in the treatment group was very significant (P < 0.01). The difference between the posttreatment mean rates of the treatment group and the control group was also significant.
CONCLUSIONS: Sequential therapy of p53 gene transcatheter arterial infusion was safe and could prolong the survival time of the patients. The biological study will play a positive role in guiding and monitoring the aspects of dosage selection and judgment of therapeutic efficacy.

Zheng L, Gong W, Liang P, et al.
Effects of AFP-activated PI3K/Akt signaling pathway on cell proliferation of liver cancer.
Tumour Biol. 2014; 35(5):4095-9 [PubMed] Related Publications
This study aims to investigate effects of alpha-fetoprotein (AFP)-activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway on hepatocellular carcinoma cell proliferation. Active cirrhosis patients after hepatitis B infection (n = 20) and viral hepatitis patients with hepatocellular carcinoma (HCC) (n = 20) were selected as the subjects of the present study. Another 20 healthy subjects were selected as the control group. The serum AFP expression and liver tissue PI3K and Akt gene mRNA expression were detected. The hepatoma cell model HepG2 which had a stable expression of AFP gene was used. Real-time quantitative PCR and Western blot and other methods were used to analyze the intracellular PI3K and Akt protein levels. Compared with control group and cirrhosis group, the serum AFP levels in HCC group significantly increased, and the tissue PI3K and Akt mRNA expression also significantly increased. HepG2 cells were intervened using AFP, in which the PIK and Akt protein expression significantly increased. After intervention by use of AFP monoclonal antibodies or LY294002 inhibitor, the PIK and Akt protein expression in HepG2 cell was significantly decreased (P < 0.05). AFP can promote the proliferation of hepatoma cells via activation of PI3K/Akt signaling pathway.

Liu X, Huang Y, Yang D, et al.
Overexpression of TRIM24 is associated with the onset and progress of human hepatocellular carcinoma.
PLoS One. 2014; 9(1):e85462 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The survival and colonization of tumor cells at new locations involve a variety of complex genetic, epigenetic, and microenvironmental factors. TRIM24 was originally named transcription intermediary factor 1-alpha (TIF1α), which was associated with cellular proliferation and was an oncogene in tumor development. Here we provide the first evidence of the expression profile and clinicopathological significance of TRIM24 in patients with hepatocellular carcinoma (HCC). Immunohistochemistry was employed to determine the expression level of TRIM24 in HCC tissues and noncancerous liver tissues. Elevated TRIM24 level was found in 61.4% HCC samples (51/83) correlating with AFP (P = 0.036), poor differentiation (P = 0.004), intrahepatic metastasis (P = 0.004), recurrence (P = 0.000006), and shorter tumor-free survival time (P = 0.002). Small interfering RNA induced down-regulation of TRIM24 promoted apoptosis in HCC cell line HepG2. Moreover, western blotting analysis revealed that knockdown of TRIM24 increased the protein levels of p53, Bax, and Caspase-8, and decreased Bcl-2, Survivin, Cyclin D1, and CDK4. Depletion of TRIM24 decreased Snail, Slug, β-catenin, and Vimentin, and increased E-cadherin expression, which suggested the involvement of TRIM24 in EMT. These results indicated that TRIM24 plays an important role in the pathogenesis of human HCC.

Yan C, Yang M, Li Z, et al.
Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter.
Biomaterials. 2014; 35(9):3035-43 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) are promising vehicles for delivering therapeutic agents in tumor therapy. Human umbilical cord-derived mesenchymal stem cells (HUMSCs) resemble bone marrow-derived MSCs with respect to hepatic differentiation potential in injured livers in animals, while their hepatic differentiation under the hepatocarcinoma microenvironment is unclear. In this study, HUMSCs were isolated and transduced by lentiviral vectors coding the soluble human tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) gene driven by alpha-fetoprotein (AFP) promoter to investigate the therapeutic effects of these HUMSC against orthotopically implanted hepatocarcinoma in mice. We showed that HUMSCs can be transduced by lentivirus efficiently. HUMSCs developed cuboidal morphology, and expressed AFP and albumin in a two-step protocol. HUMSCs were capable of migrating to hepatocarcinoma in vitro as well as in vivo. In the orthotopical hepatocarcinoma microenvironment, the AFP promoter was activated during the early hepatic differentiation of HUMSCs. After intravenous injected, MSC.AFPILZ-sTRAIL expressed sTRAIL exclusively at the tumor site, and exhibited significant antitumor activity. This effect was stronger when in combination with 5-FU. The treatment was tolerated well in mice. Collectively, our results provide a potential strategy for targeted tumor therapy relying on the use of the tumor tropism and specific differentiation of HUMSCs as vehicles.

Mohamed FZ, Hussein YM, El-Deen IM, Sabea MS
Cyclooxygenase-2 single-nucleotide polymorphisms and hepatocellular carcinoma in Egypt.
Mol Biol Rep. 2014; 41(3):1461-8 [PubMed] Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is a worldwide neoplasm for which early diagnosis is difficult and the prognosis is usually poor. Overexpression of cyclooxygenase 2 (COX-2) has been suggested to be associated with hepatocarcinogenesis. Although several COX-2 inhibitors have been used in hepatoma therapy, the genetic background between COX-2 and HCC remains largely unknown. In this study, the association of genotypic polymorphisms in COX-2 with HCC was investigated. 25 healthy individuals served as control (group I), group II: 50 HCV infection patients without any complications, group III: 50 HCV infected patients complicated with cirrhosis and group IV: 75 HCV infected patients complicated with (45 localized and 30 metastatic) HCC from Zagazig University Hospital in Egypt were genotyped by a PCR-RFLP method. The results showed that, no differences in distribution between the HCC and other groups were found. We found -1195A allele carriers had a higher risk of HCC with HCV infection. As regard the obtained results of serum AFU, a significant increase was detected in HCC as compared with cirrhosis, hepatitis and healthy control groups (p < 0.001). Concerning the obtained results of serum AFP, when HCC group was compared with cirrhosis, hepatitis and healthy controls, a significant increase was observed (p < 0.001).
IN CONCLUSION: identification of SNP in COX-2 gene promoter and evaluation of serum AFU and AFP give a red light in early detection of HCC which may be reduce its fatal incidence.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. AFP, Cancer Genetics Web: http://www.cancer-genetics.org/AFP.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 28 February, 2015     Cancer Genetics Web, Established 1999