GPC3; glypican 3 (Xq26.1)

Gene Summary

Gene:GPC3; glypican 3
Aliases: SGB, DGSX, MXR7, SDYS, SGBS, OCI-5, SGBS1, GTR2-2
Summary:Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Updated:14 December, 2014


What does this gene/protein do?
Show (40)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 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.

  • Smoking
  • Wnt Proteins
  • X Chromosome
  • Neoplasm Proteins
  • DNA Sequence Analysis
  • Transfection
  • Oligonucleotide Array Sequence Analysis
  • Lung Cancer
  • DNA Methylation
  • Cancer Gene Expression Regulation
  • Wnt Signaling Pathway
  • Immunohistochemistry
  • Vesicular Transport Proteins
  • Hepatocellular Carcinoma
  • Membrane Proteins
  • Tumor Markers
  • Tissue Array Analysis
  • Heparan Sulfate Proteoglycans
  • Transcription
  • Western Blotting
  • Polymerase Chain Reaction
  • Breast Cancer
  • Gene Expression
  • Promoter Regions
  • Gene Expression Profiling
  • Differential Diagnosis
  • Childhood Cancer
  • Thyroid Cancer
  • Genetic Predisposition
  • Glypicans
  • Single Nucleotide Polymorphism
  • Wilms Tumour
  • Cell Proliferation
  • Risk Factors
  • Mutation
  • GPC3
  • Translocation
  • DNA Primers
  • Staging
  • Liver Cancer
  • Messenger RNA
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (7)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Liver CancerGPC3 and Liver Cancer View Publications245
Lung CancerGPC3 and Lung Cancer View Publications13
-GPC3 targeted Immunotherapy Therapy View Publications12
Wilms TumourGPC3 expression in Wilms' Tumor View Publications8
Breast CancerGPC3 and Breast Cancer View Publications8
Thyroid CancerGPC3 and Thyroid Cancer View Publications3
-GPC3 Expression in Neuroblastoma View Publications4

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

Related Links

Latest Publications: GPC3 (cancer-related)

Kido T, Lo RC, Li Y, et al.
The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma.
Hum Pathol. 2014; 45(9):1847-58 [PubMed] Related Publications
There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus-associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners.

Related: Liver Cancer FOXM1

Knelson EH, Gaviglio AL, Nee JC, et al.
Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth.
J Clin Invest. 2014; 124(7):3016-31 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma prognosis is dependent on both the differentiation state and stromal content of the tumor. Neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here, we identified critical growth-limiting components of the differentiating stroma secretome and designed a potential therapeutic strategy based on their central mechanism of action. We demonstrated that expression of heparan sulfate proteoglycans (HSPGs), including TβRIII, GPC1, GPC3, SDC3, and SDC4, is low in neuroblasts and high in the Schwannian stroma. Evaluation of neuroblastoma patient microarray data revealed an association between TGFBR3, GPC1, and SDC3 expression and improved prognosis. Treatment of neuroblastoma cell lines with soluble HSPGs promoted neuroblast differentiation via FGFR1 and ERK phosphorylation, leading to upregulation of the transcription factor inhibitor of DNA binding 1 (ID1). HSPGs also enhanced FGF2-dependent differentiation, and the anticoagulant heparin had a similar effect, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-desulfated heparin (ODSH) as a differentiating agent, and treatment of orthotopic xenograft models with ODSH suppressed tumor growth and metastasis without anticoagulation. These studies support heparan sulfate signaling intermediates as prognostic and therapeutic neuroblastoma biomarkers and demonstrate that tumor stroma biology can inform the design of targeted molecular therapeutics.

Related: FGF2 Neuroblastoma FGFR1 gene Signal Transduction

Morris KL, Tugwood JD, Khoja L, et al.
Circulating biomarkers in hepatocellular carcinoma.
Cancer Chemother Pharmacol. 2014; 74(2):323-32 [PubMed] Related Publications
PURPOSE: Our aims are to determine levels of circulating cellular and protein biomarkers in hepatocellular carcinoma (HCC) patients and to analyse any relationships with clinical parameters.
METHODS: Fifty-four consenting patients were recruited. Circulating tumour cells (CTCs) were enumerated (by CellSearch) and characterised via filtration [by isolation by size of epithelial tumour cells (ISET)] with downstream immunohistochemistry (IHC). Glypican-3 (GPC3) expression in tumour biopsies and CTCs (by IHC) was compared, and levels of circulating caspase-cleaved and full-length cytokeratin 18 (CK18, measured using M30 and M65 ELISAs) were examined as a putative prognostic factor and marker of tumour burden.
RESULTS: CTCs were identified in 14 out of 50 (28%) patients by CellSearch and in 19 out of 19 (100%) patients by ISET. The presence of GPC3-positive CTCs by ISET was 100% concordant with the presence of GPC3-positive cells in the original tumour (n = 5). No statistically significant correlations were observed between CTC number and clinical characteristics, although trends were noted between CTC subtypes, Child-Pugh score and tumour node metastasis stage. Serum M30 and M65 levels (as continuous variables) significantly correlated with overall survival (OS) in a univariate analysis (p = 0.003 and p < 0.001, respectively); M65 levels remained statistically significant in a multivariate analysis (p = 0.029).
CONCLUSIONS: This is the first study to detect GPC3-positive CTCs in HCC, important for drug development with this target. The significant association of circulating CK18 with OS in HCC further exemplifies the utility of circulating biomarkers in cancer.

Related: Liver Cancer

Magers MJ, Kao CS, Cole CD, et al.
"Somatic-type" malignancies arising from testicular germ cell tumors: a clinicopathologic study of 124 cases with emphasis on glandular tumors supporting frequent yolk sac tumor origin.
Am J Surg Pathol. 2014; 38(10):1396-409 [PubMed] Related Publications
Somatic-type malignancies (SMs) in patients with testicular germ cell tumors (GCT) are rare and mostly attributed to "transformation" of teratoma, although yolk sac tumor (YST) origin has also been proposed. We studied 124 cases of "SM" of testicular GCT origin from 106 patients to evaluate their morphology, immunohistochemical features (especially the utility of SALL4), and relationship to YST. Primitive neuroectodermal and nephroblastomatous tumors were excluded because of prior studies. Patients ranged in age from 15 to 68 years (mean, 33 y). The tumors ranged from 0.7 to 30 cm (mean, 7.6 cm) and involved the retroperitoneum (64%), abdomen/pelvis (10%), lung (10%), mediastinum (6%), supraclavicular region/neck (4%), testis (4%), and thigh (1%). Most initial diagnoses were sarcomas (n=68) or carcinomas (n=51). On review and immunohistochemical analysis, 7 of 45 adenocarcinomas were reclassified as glandular YSTs (GYST) on the basis of glypican-3 (GPC3) and/or α-fetoprotein positivity and scant/absent reactivity for EMA and CK7. These occasionally (29%) had subnuclear and sometimes supranuclear vacuoles (endometrioid-like), whereas adenocarcinomas were more frequently mucinous (17%) or enteric-type (11%) than endometrioid-like (9%). Both expressed CDX2 frequently (83% and 63%, respectively). MUC protein 2, 4, 5, and 6 expression was more common in adenocarcinomas (7% to 36%) than in GYSTs (0% to 20%) but was infrequent. Both were often positive for SALL4, BerEP4, and MOC31; all were negative for TTF-1. On follow-up (GYST: range, 23 to 169 mo; mean, 81mo; adenocarcinoma: range, 1 to 170 mo; mean, 55 mo), 50% and 33% of patients with GYST and adenocarcinoma, respectively, died of disease. We reclassified 26 of 76 sarcomatoid tumors as sarcomatoid YSTs (SYST) on the basis of positive reactivity for both AE1/3 and GPC3. These tumors often had spindled and epithelioid cells in a fibromyxoid stroma. SYSTs were often (60%) SALL4 positive, whereas sarcomas were all negative. On follow-up (SYST: range, 1 to 259 mo; mean, 62 mo; sarcoma: range, 1 to 327 mo; mean, 70 mo), 50% and 29% of patients with SYST and sarcoma, respectively, died of disease, with most mortality occurring in those with high-grade tumors. We conclude that, on the basis of a panel of immunoreactivities, a significant number of "SMs" in testicular GCT patients are more accurately classified as either GYSTs or SYSTs. Ambiguous glandular tumors should be evaluated for GPC3, α-fetoprotein, CK7, and EMA reactivity and sarcomatoid ones for GPC3, AE1/3, and SALL4 reactivity.

Related: Germ Cell Tumors Testicular Cancer

Li SQ, Lin J, Qi CY, et al.
GPC3 DNA vaccine elicits potent cellular antitumor immunity against HCC in mice.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):278-84 [PubMed] Related Publications
BACKGROUND/AIMS: DNA-based tumor vaccine immunotherapy which elicits exclusively cellular immune response against cancer cells in an antigen-specific fashion has been documented to be an effective treatment for cancers in the past decade. Glypican 3 (GPC3) is especially overexpressed in hepatocellular carcinoma (HCC), but not in benign liver lesions and normal adult tissues, which makes it an ideal tumor antigen designed for HCC immunotherapy.
METHODOLOGY: We constructed a GPC3 cDNA vaccine by using a recombinant plasmid encoding murine GPC3 cDNA for treatment of HCC in a C57BL/6 mouse model. The specificity and effectiveness of anti-tumor immunity were assessed in vitro and in vivo studies.
RESULTS: In vitro studies showed that GPC3 DNA vaccine induced potent specific cytotoxic T lymphoctyes (CTLs) immune response against C57BL/6 homogenous HCC cell line Hepa 1-6 (GPC3+). However, there was no detectable immune response against GPC3-negative SP 2/0 cells and Sk-Hep-1 cells. In vivo study indicated that GPC3 DNA vaccine could significantly suppress homogenous tumor growth and prolong survival time of tumor bearing mice.
CONCLUSIONS: This study demonstrated the first time that the GPC3 DNA vaccine could elicit specific and effective cellular antitumor immunity against GPC3 HCC. This may provide an alternative option for immunotherapy of HCC.

Related: Liver Cancer

Osada M, Aishima S, Hirahashi M, et al.
Combination of hepatocellular markers is useful for prognostication in gastric hepatoid adenocarcinoma.
Hum Pathol. 2014; 45(6):1243-50 [PubMed] Related Publications
Hepatoid or α-fetoprotein (AFP)-producing adenocarcinomas of stomach growing in a solid pattern are highly aggressive tumors. It is difficult to detect hepatoid differentiation solely based on findings from hematoxylin and eosin stainings, especially in small biopsy specimens. Gastric adenocarcinomas with hepatoid differentiation should be distinguished from solid-type gastric adenocarcinoma because of their different biological behavior. We immunohistochemically analyzed hepatocellular markers (AFP, glypican 3, and Hepatocyte paraffin 1 [HepPar-1]) and possible markers of gastric hepatoid adenocarcinoma (Sal-like protein 4 [SALL4] and palate, lung, and nasal epithelium carcinoma-associated protein [PLUNC]) to detect hepatoid differentiation in 45 gastric hepatoid adenocarcinomas and 47 nonhepatoid solid-type poorly differentiated adenocarcinomas. There were a higher incidence of vascular invasion (P = .0055) and distant metastasis (P = .0458) in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. AFP, SALL4, HepPar-1, and glypican 3 were significantly higher in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. All 5 markers were positive in both the hepatoid/solid and the tubular component. In hepatoid adenocarcinoma, the frequency of distant metastasis was significantly higher in SALL4-negative cases than in SALL4-positive cases (P = .0381). HepPar-1 was associated with liver metastasis (P = .0452). PLUNC was correlated with lymph node metastasis (P = .0375). There was a significant difference in the survival rate between HepPar-1-positive and HepPar-1-negative groups (P = .0437). The coexpression of PLUNC and SALL4 and the other coexpression of HepPar-1 and PLUNC were associated with poorer prognosis (P = .0181 and P = .0443, respectively). AFP, SALL4, HepPar-1, and glypican 3 are useful for the detection of hepatoid differentiation. A combination of PLUNC, HepPar-1, and SALL4 could be a reliable prognostic indicator in hepatoid adenocarcinoma of the stomach.

Related: Stomach Cancer Gastric Cancer

Brychtova V, Zampachova V, Hrstka R, et al.
Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma.
Exp Mol Pathol. 2014; 96(3):375-81 [PubMed] Related Publications
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulfide isomerases. Since there is little information on how AGR3 is expressed in normal and diseased tissues and what its exact function is, we analyzed its expression pattern in normal liver and tumor tissue of ICC and HCC. The immunohistochemical analysis in normal tissue revealed specific AGR3 expression in intrahepatic bile duct cholangiocytes which was not present in liver hepatocytes. Consequently we analyzed AGR3 expression in 74 representative samples of puncture biopsies, tissue excisions and resection specimens from which 48 samples were diagnosed as HCC and 26 as ICC. Our results showed AGR3 expression negative and weakly positive respectively in hepatocellular carcinomas compared to stronger AGR3 positivity in cholangiocellular carcinomas. AGR3 expression statistically significantly correlated to acid mucopolysaccharide expression and negatively correlated to glypican-3 expression. We conclude that according to receiver operating characteristics (ROC) analysis AGR3 expression is relatively specific for ICC and is potentially linked to mucosecretion, which may indicate potential implication in treatment resistance.

Related: Liver Cancer

Li M, Bao L, Cai H, et al.
[Clinicopathologic features of ovarian clear cell carcinoma [correction of epithelial ovarian cancer] with yolk sac tumor component: report of a case].
Zhonghua Bing Li Xue Za Zhi. 2014; 43(2):127-8 [PubMed] Related Publications

Marquez BV, Zheleznyak A, Lapi SE
Glypican-3-targeted 89Zr PET imaging of hepatocellular carcinoma: where antibody imaging dares to tread.
J Nucl Med. 2014; 55(5):708-9 [PubMed] Related Publications

Related: Liver Cancer

Wands JR, Kim M
WNT/β-catenin signaling and hepatocellular carcinoma.
Hepatology. 2014; 60(2):452-4 [PubMed] Related Publications

Yao M, Wang L, Dong Z, et al.
Glypican-3 as an emerging molecular target for hepatocellular carcinoma gene therapy.
Tumour Biol. 2014; 35(6):5857-68 [PubMed] Related Publications
Glypican-3 (GPC-3), a membrane-associated heparan sulfate proteoglycan, plays a crucial role in cell proliferation and metastasis, particularly in hepatocellular carcinoma (HCC) progression, and perhaps is a valuable target for its gene therapy. However, its mechanism remains to be explored. In the present study, the biological behaviors of HCC cells were investigated by interfering GPC-3 gene transcription. After the cells were transfected with specific GPC-3 short hairpin RNA (shRNA), the inhibition of GPC-3 expression was 75.6 % in MHCC-97H or 73.8 % in Huh7 cells at mRNA level; the rates of proliferation and apoptosis were 53.6 and 60.5 % in MHCC-97H or 54.9 and 54.4 % in Huh7 cells, with the cell cycles arrested in the G1 phase; the incidences of cell migration, metastasis, and invasion inhibition were 80.1, 56.4, and 69.1 % in MHCC-97H or 80.9, 59.6, and 58.3 % in Huh7 cells, respectively. The cell biological behaviors were altered by silencing GPC-3 with down-regulation of β-catenin, insulin-like growth factor-II and vascular endothelial growth factor, and Gli1 up-regulation. The cell proliferation was significantly inhibited (up to 95.11 %) by shRNA plus anti-cancer drugs, suggesting that GPC-3 gene should be a potential target for promoting hepatoma cell apoptosis and inhibiting metastasis through the Wnt/β-catenin and Hh singling pathways.

Related: IGF2 Liver Cancer VEGFA CTNNB1 gene

Sham JG, Kievit FM, Grierson JR, et al.
Glypican-3-targeted 89Zr PET imaging of hepatocellular carcinoma.
J Nucl Med. 2014; 55(5):799-804 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Hepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of (89)Zr-conjugated monoclonal antibody against GPC3 ((89)Zr-αGPC3) for intrahepatic tumor localization using PET.
METHODS: Polymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts.
RESULTS: (89)Zr-αGPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 ± 86.6 percentage injected dose [%ID]/g) compared with background liver (27.5 ± 1.6 %ID/g). Tumor-to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (<1 mm) showed lower peak uptake (42.5 ± 6.4 %ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 ± 87.6 %ID/g) compared with control RH7777 tumors (3.9 ± 1.3 %ID/g, P < 0.01), indicating antigen specificity by (89)Zr-αGPC3. HepG2 tumor treated with unlabeled αGPC3 or heat-denatured (89)Zr-αGPC3 demonstrated tumor activity (2.1 %ID/g) comparable to that of control xenografts, confirming antibody dependency.
CONCLUSION: This study demonstrated the feasibility of using (89)Zr-αGPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation.

Related: Monoclonal Antibodies Liver Cancer

Ikeda M, Ohkawa S, Okusaka T, et al.
Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma.
Cancer Sci. 2014; 105(4):455-62 [PubMed] Related Publications
GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose-limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C-reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose-proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long-term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma.

Related: Monoclonal Antibodies Liver Cancer

Wang FH, Wen JM, Vong HT, Yip YC
[Glypican 3 expression in hepatoblastoma and its diagnostic implication].
Zhonghua Bing Li Xue Za Zhi. 2013; 42(12):806-9 [PubMed] Related Publications
OBJECTIVE: To explore the expression and diagnostic significance of glypican-3 (GPC3) in hepatoblastoma.
METHODS: Five tissue microarray paraffin blocks were constructed to include 54 cases of hepatoblastoma. The tumor tissue samples were obtained from 3 surgical biopsies, 33 needle biopsies, 5 stage I resection tumors, and 13 stage II resection tumors after transcatheter arterial chemoembolization. Ten samples of non-neoplastic hepatic tissue adjacent to tumor were used as control. Immunohistochemical staining of GPC3 (clone 1G12) was performed. Among the 54 cases of hepatoblastoma, 22 cases were fetal subtype, 24 cases were mixed fetal and embryonal subtype and 8 cases were mixed epithelial and mesenchymal type.
RESULTS: GPC3 was positive in fetal epithelial cells (54/54, 100%), but negative or weakly positive in embryonic epithelial cells in all cases of hepatoblastoma. Undifferentiated small cells and all mesenchymal components were negative for the expression. Non-neoplastic hepatocytes adjacent to tumor were negative for GPC3 expression (0/10) .
CONCLUSIONS: Fetal epithelial components of hepatoblastoma express GPC3 protein detectable by immunohistochemistry. Normal hepatocytes after birth, small cell undifferentiated and embryonic epithelial components of hepatoblastoma do not or weakly express GPC3 protein. Therefore, GPC3 immunohistochemistry offers a valuable aid to the diagnosis of hepatoblastoma in infants and children.

Related: Liver Cancer Childhood Liver Cancer

Gong L, Wei LX, Ren P, et al.
Dysplastic nodules with glypican-3 positive immunostaining: a risk for early hepatocellular carcinoma.
PLoS One. 2014; 9(1):e87120 [PubMed] Free Access to Full Article Related Publications
Glypican-3 (GPC3) has been reported to be a novel serum and histochemical marker for HCC. The positivity or negativity for GPC3 in hepatic precancerous lesions, such as dysplastic nodules (DN), has also been described. Moreover, our previous studies have demonstrated that some DN in liver cirrhosis represent monoclonal hyperplasia, and confirmed their neoplastic nature. However, additional studies must be performed to investigate further the relationship between DN with GPC3 positivity and HCC. Thus, we first investigated the expression of GPC3 in 136 HCC and 103 small DN (less than 1 cm in diameter) by immunohistochemical staining and determined the clonality of 81 DN from female patients using X-chromosome inactivation mosaicism and polymorphism of androgen receptor (AR) gene. Then we examined these samples for chromosomal loss of heterozygosity (LOH) at 11 microsatellite polymorphism sites. The results demonstrated that GPC3 immunoreactivity was detected in 103 of 136 HCC (75.7%) and 19 of 103 DN (18.4%), and the positive ratio correlated with HBsAg positivity. Clonality assays showed that 15 GPC3-positive DN from female patients, including 12 high-grade DN (HGDN), and 28 (42.4%) of 66 GPC3-negative DN, were monoclonal. In addition, among 19 GPC3-positive DN, chromosomal LOH was found at loci D6S1008 (100%, 19/19), D8S262 (52.6%, 10/19) and D11S1301 (57.9%, 11/19). However, the LOH frequency in GPC3-negative DN was 5.95% (5/84), 23.8% (20/84), and 4.76% (4/84) in three loci, respectively. Thus, we concluded that GPC3-positive DN, especially GPC3-positive HGDN, was really a late premalignant lesion of HCC.

Related: Liver Cancer Polymorphisms

Gao W, Kim H, Feng M, et al.
Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy.
Hepatology. 2014; 60(2):576-87 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
UNLABELLED: Wnt signaling is important for cancer pathogenesis and is often up-regulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as coreceptors or modulators of Wnt activation. Glypican-3 (GPC3) is an HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors, and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/β-catenin signaling in these cells. Then we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and nonsulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/β-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/β-catenin signaling in HCC cells and had potent antitumor activity in vivo.
CONCLUSION: An antibody directed against the heparan sulfate of a proteoglycan shows efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy.

Related: Monoclonal Antibodies Liver Cancer CTNNB1 gene

Chiba T, Suzuki E, Yuki K, et al.
Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners.
PLoS One. 2014; 9(1):e84807 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Tumor-initiating cells (TICs) play a central role in tumor development, metastasis, and recurrence. In the present study, we investigated the effect of disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, toward tumor-initiating hepatocellular carcinoma (HCC) cells. DSF treatment suppressed the anchorage-independent sphere formation of both HCC cells. Flow cytometric analyses showed that DSF but not 5-fluorouracil (5-FU) drastically reduces the number of tumor-initiating HCC cells. The sphere formation assays of epithelial cell adhesion molecule (EpCAM)(+) HCC cells co-treated with p38-specific inhibitor revealed that DSF suppresses self-renewal capability mainly through the activation of reactive oxygen species (ROS)-p38 MAPK pathway. Microarray experiments also revealed the enrichment of the gene set involved in p38 MAPK signaling in EpCAM(+) cells treated with DSF but not 5-FU. In addition, DSF appeared to downregulate Glypican 3 (GPC3) in a manner independent of ROS-p38 MAPK pathway. GPC3 was co-expressed with EpCAM in HCC cell lines and primary HCC cells and GPC3-knockdown reduced the number of EpCAM(+) cells by compromising their self-renewal capability and inducing the apoptosis. These results indicate that DSF impaired the tumorigenicity of tumor-initiating HCC cells through activation of ROS-p38 pathway and in part through the downregulation of GPC3. DSF might be a promising therapeutic agent for the eradication of tumor-initiating HCC cells.

Related: Liver Cancer

Magistri P, Leonard SY, Tang CM, et al.
The glypican 3 hepatocellular carcinoma marker regulates human hepatic stellate cells via Hedgehog signaling.
J Surg Res. 2014; 187(2):377-85 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) frequently represents two diseases as it often arises in the setting of cirrhosis caused by the proliferation and activation of hepatic stellate cells (HSCs). Previously, we identified that Hedgehog (Hh) signaling regulates HSC viability and fibrinogenesis, as well as HCC tumorigenesis. Although it is increasingly recognized that HSCs and HCCs communicate via paracrine signaling, Hh's role in this process is just emerging. We hypothesized that a secreted HCC tumor marker and Hh mediator, glypican 3 (GPC3), may regulate HSC.
METHODS: Using three human HCC lines (Hep3B, PLC/PRF/5 and SK-Hep-1) and one Hh-responsive human HSC line (LX-2), we developed two in vitro models of HCC-to-HSC paracrine signaling using a Transwell coculture system and HCC-conditioned media. We then evaluated the effects of these models, as well as GPC3, on HSC viability and gene expression.
RESULTS: Using our coculture and conditioned media models, we demonstrate that the three HCC lines decrease HSC viability. Furthermore, we demonstrate that recombinant GPC3 dose-dependently decreases the LX-2 viability while inhibiting the expression of Hh target genes that regulate HSC viability. Finally, GPC3's inhibitory effects on cell viability and Hh target gene expression are partially abrogated by heparin, a competitor for GPC3 binding.
CONCLUSIONS: For the first time, we show that GPC3, an HCC biomarker and Hh mediator, regulates human HSC viability by regulating Hh signaling. This expands on existing data suggesting a role for tumor-stroma interactions in the liver and suggests that GPC3 plays a role in this process.

Related: Apoptosis Liver Cancer Signal Transduction

Saad Y, El-Serafy M, Eldin MS, et al.
New genetic markers for diagnosis of hepatitis C related hepatocellular carcinoma in Egyptian patients.
J Gastrointestin Liver Dis. 2013; 22(4):419-25 [PubMed] Related Publications
BACKGROUND AND AIM: Early detection of hepatocellular carcinoma (HCC) enhances effective and curative management. New genetic markers with distinct diagnostic ability are required.
AIM: determine the expression of GPC3, PEG10, SERPINI1, MK and QP-C in the peripheral blood of HCC patients.
METHODS: 74 HCV patients were recruited and divided into three groups; chronic hepatitis (I), liver cirrhosis (II) and HCC (III). Demographics, laboratory and imaging data were collected. Child score and metastatic work up were completed. The expression of the five candidate genes in the peripheral blood was performed by qRT-PCR assay.
RESULTS: Groups were gender matched, age in group I was significantly lower than in groups II and III (37.7 vs 50.4 and 55.6, p value <0.005). CHILD score; group II and III A/B/C = (7/5/6) and (20/6/3). AFP was significantly higher in group III than I and II (204 vs 3.9 and 6.9, p < 0.01). In HCC group 69% of the lesions were < 5 cm, and had 1-2 nodules; 14% had metastases. GPC3, PEG10, SERPINI1 and MK mRNA were significantly higher in the HCC group compared to the other groups while QP-C mRNA was higher in chronic hepatitis C group compared to other groups. The gene expression values in HCC patients were independent of the tumor size, AFP levels or extrahepatic metastasis. Combined measurement of the five gene markers showed 100% sensitivity and 33% specificity, 48% PPV and 100% NPV.
CONCLUSION: GPC3, PEG10, SERPINI1 and MK are genetic markers that can represent a useful tool for detection of HCC.

Related: Cancer Screening and Early Detection Liver Cancer

Bao L, Chandra PK, Moroz K, et al.
Impaired autophagy response in human hepatocellular carcinoma.
Exp Mol Pathol. 2014; 96(2):149-54 [PubMed] Related Publications
BACKGROUND: Autophagy is a cellular lysosomal degradation mechanism that has been implicated in chronic liver diseases and hepatocellular carcinoma (HCC). Association of autophagy defect with the development of human HCC has been shown in transgenic mouse model.
AIM: We performed this study to verify whether a defect in autophagy would play a role in human hepatocellular carcinoma (HCC).
METHODS: Archival tissue sections of 20 patients with HCC with or without hepatitis C virus (HCV) infection were studied. All slides were immunostained using monoclonal antibodies to p62 and glypican-3 with appropriate positive and negative controls. The expression of p62 and glycican-3 in the HCC and the surrounding non-tumor was semiquantitated. The cytoplasmic staining was graded as negative, weak or strong.
RESULTS: Positive p62 staining was found in 20 out of 20 (100%) HCCs and negative staining was observed in 20 out of 20 non-tumor areas and cirrhotic nodules. Positive glypican-3 staining was found in 70% of HCCs and negative staining was seen in all non-tumor areas. An autophagy defect leading to increased expression of p62 and glypican-3 was also seen in the HCC cell line (Huh-7.5), but not in the primary human hepatocytes. Activation of cellular autophagy in Huh-7.5 cells efficiently cleared p62 and glypican-3 expression and inhibition of autophagy induced the expression of p62 and glypican-3.
CONCLUSIONS: This study shows that p62 is increased in HCC compared to the surrounding non-tumorous liver tissue suggesting that human HCCs are autophagy defective. We provide further evidence that glypican-3 expression in HCC may also be related to defective autophagy. Our study indicates that p62 immunostain may represent a novel marker for HCC.

Related: Liver Cancer

Liu XF, Hu ZD, Liu XC, et al.
Diagnostic accuracy of serum glypican-3 for hepatocellular carcinoma: a systematic review and meta-analysis.
Clin Biochem. 2014; 47(3):196-200 [PubMed] Related Publications
OBJECTIVE: Many individual studies have evaluated the diagnostic efficiency of serum glypican-3 (GPC-3) for diagnosing hepatocellular carcinoma (HCC), but the results have been inconsistent. The aim of present study was to meta-analyze the overall diagnostic accuracy of serum GPC-3 for diagnosing HCC.
DESIGN AND METHODS: English language studies which evaluated the diagnostic performance of GPC-3 and published before March 22, 2013 were retrieved. The quality of the studies was assessed by revised QUADAS tools. The performance characteristics were pooled and determined by random-effects models.
RESULTS: Twelve studies with a total of 898 HCC patients and 835 non-HCC patients were included. For the studies in which the majority of reference participants had HBV or HCV infections, the overall diagnostic sensitivity and specificity were 0.53 (95% CI: 0.49-0.57) and 0.77 (95% CI: 0.74-0.81), respectively. The area under summary receiver operating characteristic (sROC) curves (AUC) was 0.82. The major design deficiencies of included studies were differential verification bias, and a lack of clear exclusion and inclusion criteria.
CONCLUSIONS: GPC-3 has moderate diagnostic accuracy for HCC. Due to the design limitations, results in published studies should be carefully interpreted. In addition, more well-designed studies with large sample sizes should be performed to rigorously evaluate the diagnostic value of the GPC-3.

Related: Liver Cancer

Melson J, Li Y, Cassinotti E, et al.
Commonality and differences of methylation signatures in the plasma of patients with pancreatic cancer and colorectal cancer.
Int J Cancer. 2014; 134(11):2656-62 [PubMed] Related Publications
Profiling of DNA methylation status of specific genes is a way to screen for colorectal cancer (CRC) and pancreatic cancer (PC) in blood. The commonality of methylation status of cancer-related tumor suppressor genes between CRC and PC is largely unknown. Methylation status of 56 cancer-related genes was compared in plasma of patients in the following cohorts: CRC, PC and healthy controls. Cross validation determined the best model by area under ROC curve (AUC) to differentiate cancer methylation profiles from controls. Optimal preferential gene methylation signatures were derived to differentiate either cancer (CRC or PC) from controls. For CRC alone, a three gene signature (CYCD2, HIC and VHL) had an AUC 0.9310, sensitivity (Sens) = 0.826, specificity (Spec) = 0.9383. For PC alone, an optimal signature consisted of five genes (VHL, MYF3, TMS, GPC3 and SRBC), AUC 0.848; Sens = 0.807, Spec = 0.666. Combined PC and CRC signature or "combined cancer signature" was derived to differentiate either CRC and PC from controls (MDR1, SRBC, VHL, MUC2, RB1, SYK and GPC3) AUC = 0.8177, Sens = 0.6316 Spec = 0.840. In a validation cohort, N = 10 CRC patients, the optimal CRC signature (CYCD2, HIC and VHL) had AUC 0.900. In all derived signatures (CRC, PC and combined cancer signature) the optimal panel used preferential VHL methylation. In conclusion, CRC and PC differ in specific genes methylated in plasma other than VHL. Preferential methylation of VHL is shared in the optimal signature for CRC alone, PC alone and combined PC and CRC. Future investigations may identify additional methylation markers informative for the presence of both CRC and PC.

Related: Colorectal (Bowel) Cancer Cancer of the Pancreas Pancreatic Cancer

Li B, Liu H, Shang HW, et al.
Diagnostic value of glypican-3 in alpha fetoprotein negative hepatocellular carcinoma patients.
Afr Health Sci. 2013; 13(3):703-9 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: The prognosis of patients with hepatocellular carcinoma(HCC) is generally very poor with a 5-year survival rate of less than 15% since most of them are diagnosed clinically at their late stage. However, the differential diagnosis between alpha fetoprotein(AFP) negative HCC and cirrhotic nodules is still difficult.
OBJECTIVES: To evaluate the diagnostic value of glypican-3(GPC3) in patients with AFP negative hepatitis B related HCC.
METHODS: The liver tissue GPC3 (GPC3L) expression was tested from 426 for surgery and 179 of needle biopsies of hepatitis B related HCC patients using immunohistochemistry staining. Serum GPC3 (GPC3S) and AFP were also measured.
RESULTS: Among surgical HCC samples, 80.0% of GPC3L expression was positive, however, in paracarcinomatous and cirrhotic nodules were negative. In needle biopsy tissues, GPC3L positively expression was in 74.9%. The sensitivity of AFP>400 µg/L was 25.4%. The GPC3S >3.5 µg/L was determined as a positive. The area of ROC curve of GPC3S was 0.68(95% CI 0.56-0.79,P<0.05) in all HCC patients,0.81 (95% CI 0.62 -0. 98, P<0.05) in AFP greater or equal to 400 µg/L and 0.64 (95% CI 0.51-0.77, P=0.051) in AFP negative patients. The GPC3S was positive in 48.8% of patients with AFP negative. No difference was observed between GPC3L/GPC3S and serum AFP.
CONCLUSIONS: GPC3 may be helpful in improving diagnosis of HCC and in differentiating diagnosis between AFP negative HCC and cirrhotic nodules.

Related: Liver Cancer

Wang Y, Yang H, Xu H, et al.
Golgi protein 73, not Glypican-3, may be a tumor marker complementary to α-Fetoprotein for hepatocellular carcinoma diagnosis.
J Gastroenterol Hepatol. 2014; 29(3):597-602 [PubMed] Related Publications
BACKGROUND AND AIM: This study aimed to evaluate the effectiveness of serum Golgi protein 73 (GP73) and Glypican-3 (GPC-3) as tumor markers for diagnosis of hepatocellular carcinoma (HCC).
METHODS: A total of 257 subjects were enrolled and consisted of 61 healthy controls, 32 hepatitis B virus carriers, 80 cirrhosis patients, and 84 HCC patients. Diagnosis was performed based on established clinical procedure. Serum GP73, GPC-3, and α-fetoprotein were measured. Receiving operating characteristic (ROC) curves were plotted to determine the sensitivity and specificity of each serum marker and their combinations.
RESULT: Serum GP73 levels were significantly increased in HCC patients. No significant differences were observed between GP73 and α-fetoprotein (AFP) as markers for HCC diagnosis. However, GP73 was more sensitive than AFP in the diagnosis of small HCC. A combination of GP73 and AFP tests increased the sensitivity and specificity for HCC diagnosis. The area under the ROC curve (AUC) of combined test was 0.93 compared with 0.88 for GP73 and 0.90 for AFP alone. GPC-3 tests were negative in all 84 HCC patients. The AUC for GPC-3 is 0.43, indicating that serum GPC-3 was not an effective tumor marker for HCC diagnosis.
CONCLUSION: Serum GP73 is a potential tumor marker for HCC diagnosis, especially for differential diagnosis of small HCC and cirrhosis. The combination of GP73 and AFP is more sensitive than AFP alone. Serum GPC-3 does not appear to be an effective tumor marker for HCC diagnosis.

Related: Liver Cancer

Gailey MP, Bellizzi AM
Immunohistochemistry for the novel markers glypican 3, PAX8, and p40 (ΔNp63) in squamous cell and urothelial carcinoma.
Am J Clin Pathol. 2013; 140(6):872-80 [PubMed] Related Publications
OBJECTIVES: To examine squamous cell carcinomas (SCCs) from diverse anatomic sites and invasive urothelial carcinomas (UCs) for expression of the oncofetal antigen glypican 3 (GPC3), the paired box transcription factor PAX8, and the ΔN isoform of p63 (p40).
METHODS: Immunohistochemistry for GPC3, PAX8, and p40 was performed on whole sections of 107 SCCs from 11 anatomic sites and 49 UCs; evaluation included extent and intensity of staining.
RESULTS: GPC3 was detected in 20% of SCCs and 12% of UCs and PAX8 in 3% of SCCs, limited to the uterine cervix, and 10% of UCs. p40 Was found in 99% of SCCs and 96% of UCs.
CONCLUSIONS: GPC3 expression is frequent in SCC/UC, awareness of which should guard against an incorrect diagnosis of hepatocellular carcinoma, while PAX8, limited in distribution, may have some use in suggesting a cervical or urothelial tract origin in a metastatic squamotransitional carcinoma of unknown primary. There is no drop-off in sensitivity for the diagnoses of SCC or UC with ΔNp63-specific immunohistochemistry, and if this performance can be extended to other applications, p40 may supplant the dominant "pan-p63" antibody clone.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology PAX8 gene

Zaakook M, Ayoub M, Sinna EA, El-Sheikh S
Role of glypican-3 immunocytochemistry in differentiating hepatocellular carcinoma from metastatic carcinoma of the liver utilizing fine needle aspiration cytology.
J Egypt Natl Canc Inst. 2013; 25(4):173-80 [PubMed] Related Publications
PURPOSE: Evaluation of the sensitivity and specificity of glypican3 (GPC3) in differentiating hepatocellular carcinoma (HCC) from metastatic carcinomas of the liver in cell block material.
PATIENTS AND METHODS: Sixty cell blocks were prepared from liver FNAs performed in the radiodiagnosis department, National Cancer Institute, in the period between August 2011 and May 2012. Cases diagnosed as hepatocellular carcinoma, or metastatic carcinoma were included in the study. Cell block sections were stained with anti GPC-3. Sensitivity, specificity, and positive and negative predictive values, of GPC3 were calculated. The final diagnosis was based on the triple approach of clinical data, radiological findings, as well as cytomorphologic features aided by GPC-3 results.
RESULTS: 70% of cases were diagnosed as HCC, and 30% as metastatic carcinomas. 95.2% of HCC cases expressed GPC3. Poorly differentiated cases showed the highest GPC3 sensitivity (100%), followed by moderately differentiated cases (96.5%), while well differentiated cases expressed GPC3 in 90% of cases. 83.3% of metastatic carcinomas were negative for GPC3. In this study, sensitivity of GPC-3 in HCC was 95.2%, specificity was 83.3%, positive and negative predictive values were 93% and 88.2% respectively, and total accuracy was 91.7%.
CONCLUSION: Immunocytochemical staining for GPC3 in cell block material is a highly sensitive and specific method capable of distinguishing HCC from the vast majority of metastatic carcinomas of the liver.

Related: Liver Cancer

Ibrahim GH, Mahmoud MA, Aly NM
Evaluation of circulating Transforming growth factor-beta1, Glypican-3 and Golgi protein-73 mRNAs expression as predictive markers for hepatocellular carcinoma in Egyptian patients.
Mol Biol Rep. 2013; 40(12):7069-75 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) incidence is fast-growing especially in countries highly prevalent with viral hepatitis. Its poor prognosis has driven the research toward the discovery of sensitive markers for early detection. We investigated the usefulness of serum Transforming growth factor-beta1 (TGF-β1), Glypican-3 (GPC3), and Golgi protein-73 (GP73) mRNAs as early biomarkers in HCC Egyptian patients chronically infected with hepatitis C virus (HCV) in comparison with serum alpha-fetoprotein (AFP). Using semi-quantitative RT-PCR and densitometry analysis, circulating TGF-β1, GPC3, and GP73 mRNAs expressions were estimated in 15 healthy adults, 15 chronic HCV (CHC) patients and 25 HCC patients. Serum GP73 expression percentage in HCC group was significantly higher than controls (100 vs. 40 %, P ≤ 0.001) and when compared to elevated serum AFP levels (100 vs. 36 %, P ≤ 0.001). TGF-β1 and GP73 expression means were also higher in HCC patients than controls and CHC patients (P < 0.05). GPC3 expression showed higher frequency in CHC patients compared to HCC group (80 vs. 28 %, P = 0.0016). According to the study cutoffs, serum TGF-β1 and GP73 mRNAs showed 60 and 96 % sensitivities for HCC diagnosis with 100 and 95 % specificities, respectively. Furthermore, elevated GP73 mRNA expression levels in early HCC were significantly increased compared to those of TGF-β1 mRNA and to high serum AFP (92.3 vs. 53.8 and 23.1 %; P = 0.03 and 0.0004, respectively). In conclusion, circulating TGF-β1 and GP73 mRNAs could be useful biomarkers for HCV-induced HCC diagnosis. Moreover, serum GP73 mRNA is sensitive for early cancer detection than AFP and TGF-β1 mRNA. However, these results need further validation studies.

Related: Liver Cancer TGFB1

Feng M, Ho M
Glypican-3 antibodies: a new therapeutic target for liver cancer.
FEBS Lett. 2014; 588(2):377-82 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation. Here, we summarize current evidence for GPC3 as a new target in liver cancer, discuss both its oncogenic function and its mode of actions for current antibodies, and evaluate potential challenges for GPC3-targeted anti-cancer therapies.

Related: Liver Cancer

Yu DD, Yao M, Chen J, et al.
[Short hairpin RNA mediated glypican-3 silencing inhibits hepatoma cell invasiveness and disrupts molecular pathways of angiogenesis].
Zhonghua Gan Zang Bing Za Zhi. 2013; 21(6):452-8 [PubMed] Related Publications
OBJECTIVE: To construct glypican-3 (GPC-3) short hairpin RNA (shRNA) and investigate the effects of GPC-3 transcription silencing on hepatoma cell invasion and angiogenesis mechanisms.
METHODS: GPC-3-specific shRNA and non-target control shRNA were constructed and transfected into the human hepatoma cell lines HepG2, MHCC-97H, and Huh7. shRNA-mediated silencing of GPC-3 expression was confirmed at the mRNA and protein levels by fluorescence quantitative reverse transcription (FQRT)-PCR and western blotting, respectively. The effect of silenced GPC-3 expression on cell proliferation was detected by EdU and sulforhodamine B assays, on migration by wound healing (scratch) assay, on invasion by transwell chamber assay, and on apoptosis by luminescence assay of caspase-3/7 activity. The effect of silenced GPC-3 expression on angiogenesis-related signaling factors was detected by FQRT-PCR (for the glioma-associated oncogene homolog-1 hedgehog signaling factor, GLI1, and the beta-catenin Wnt signaling factor, b-catenin), immunofluorescent staining (for the insulin-like growth factor-II, IGF-II), and ELISA (for the vascular endothelial growth factor, VEGF). Pairwise comparisons were made by the independent sample t-test, and multiple comparisons were made by one-way ANOVA.
RESULTS: In all cell lines, transfection with the GPC-3-specific shRNA significantly reduced GPC-3 mRNA levels (% reduction as compared to the non-target control shRNA: HepG2, 89.2+/-6.0%, t = -25.753, P less than 0.001; MHCC-97H, 75.3+/-4.9%, t = -26.487, P less than 0.001; Huh7, 73.6+/-4.6%, t = -27.607, P less than 0.001); the GPC-3 protein levels were similarly reduced. The GPC-3 shRNA-silenced cells showed significantly reduced proliferative, migratory and invasive capacities, as well as significantly increased apoptosis. The shRNA-mediated GPC-3 silencing was accompanied by significant down-regulation of b-catenin mRNA (HepG2, 46.9+/-0.6%; MHCC-97H, 67.5+/-2.7%; Huh7, 56.3+/-8.4%) and significant up-regulation of GLI1 mRNA (HepG2, 49.2+/-28.6%; MHCC-97H, 54.6+/-24.4%; Huh7, 31.6+/-15.7%). At 72 h after transfection, the HepG2 cells showed significant down-regulation of VEGF protein (54.3+/-1.5%, t = 46.746, P less than 0.001).
CONCLUSION: GPC-3 contributes to migration, invasion, angiogenesis, and apoptosis of hepatoma cells, possibly through its interactions with the Wnt/b-catenin and Hedgehog signaling pathways. GPC-3 may represent a useful target for gene silencing by molecular-based therapies to treat hepatocellular carcinoma.

Related: Apoptosis CASP3 Liver Cancer Angiogenesis and Cancer Signal Transduction VEGFA CTNNB1 gene

Greten TF, Duffy AG, Korangy F
Hepatocellular carcinoma from an immunologic perspective.
Clin Cancer Res. 2013; 19(24):6678-85 [PubMed] Article available free on PMC after 15/12/2014 Related Publications
Hepatocellular carcinoma is the third most common cancer worldwide. It is an inflammation-associated cancer. Multiple investigators have demonstrated that analysis of the tumor microenvironment may be used to predict patient outcome, indicating the importance of local immune responses in this disease. In contrast with other types of cancer, in which surgery, radiation, and systemic cytotoxic chemotherapies dominate the treatment options, in hepatocellular carcinoma locoregional treatments are widely applied. Such treatments induce rapid tumor cell death and antitumor immune responses, which may favor or impair the patients' outcome. Recent immunotherapeutic studies demonstrating promising results include trials evaluating intratumoral injection of an oncolytic virus expressing granulocyte macrophage colony-stimulating factor, glypican-3 targeting treatments, and anti-CTLA4 treatment. Although some of these novel approaches may provide benefit as single agents, there is a clear opportunity in hepatocellular carcinoma to evaluate these in combination with the standard modalities to more effectively harness the immune response.

Related: Liver Cancer


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