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, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: GPC3 (cancer-related)

Pradier MF, Reis B, Jukofsky L, et al.
Case-control Indian buffet process identifies biomarkers of response to Codrituzumab.
BMC Cancer. 2019; 19(1):278 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3), which is expressed in hepatocellular carcinoma (HCC), was tested in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. Biomarker analysis was performed to identify a responder population that benefits from treatment.
METHODS: A novel statistical method based on the Indian buffet process (IBP) was used to identify biomarkers predictive of response to treatment with Codrituzumab. The IBP is a novel method that allows flexibility in analysis design, and which is sensitive to slight, but meaningful between-group differences in biomarkers in very complex datasets RESULTS: The IBP model identified several subpopulations of patients having defined biomarker values. Tumor necrosis and viable cell content in the tumor were identified as prognostic markers of disease progression, as were the well-known HCC prognostic markers of disease progression, alpha-fetoprotein and Glypican-3 expression. Predictive markers of treatment response included natural killer (NK) cell surface markers and parameters influencing NK cell activity, all related to the mechanism of action of this drug CONCLUSIONS: The Indian buffet process can be effectively used to detect statistically significant signals with high sensitivity in complex and noisy biological data TRIAL REGISTRATION: NCT01507168 , January 6, 2012.

Zhang Y, Qiu D, Li R, et al.
Preparation of a monoclonal antibody against the carcinoembryonic antigen, glypican‑3.
Mol Med Rep. 2019; 19(5):3889-3895 [PubMed] Related Publications
The carcinoembryonic antigen, glypican‑3 (GPC3), is a putative therapeutic target and diagnostic marker of hepatoma. In the present study, a monoclonal antibody (mAb) specifically against GPC3 was obtained via cloning the sequence of GPC3 via polymerase chain reaction and inserting it into a pET16b vector prior to transfection into Escherichia coli (E. coli) BL21. BALB/c mice were immunized with 20 µg purified antigen by intrasplenic embedding. Splenocytes and mouse myeloma cells SP2/0 were fused; then, the hybridoma cells were screened by an indirect ELISA. The properties of the mAb were examined by western blotting and immunofluorescence analysis against the purified protein. The results revealed that the prokaryotic expression vector of GPC3 had been successfully generated and GPC3 was stably expressed in E. coli BL21. A stable hybridoma cell line, 2F3, was generated in the present study, which produced mAbs against GPC3. The mAb 2F3 had a high antibody titer and the isotype was identified as IgG1/κ; 2F3 hybridomas had a median chromosome number of 98. Western blot and immunofluorescence analyses revealed that 2F3 specifically recognized recombinant and native GPC3. The 2F3 clone was proposed as a stable secretor of this mAb against GPC3. The results of present study indicated that the successful preparation of recombinant GPC3 protein and an anti‑human GPC3 mouse mAb may be provide a basis for developments in the diagnosis and treatment of liver cancer.

Hazekawa M, Nishinakagawa T, Kawakubo-Yasukochi T, Nakashima M
Glypican-3 gene silencing for ovarian cancer using siRNA-PLGA hybrid micelles in a murine peritoneal dissemination model.
J Pharmacol Sci. 2019; 139(3):231-239 [PubMed] Related Publications
Small interfering RNA (siRNA) has received much attention and for possible therapeutic applications to treat incurable chronic and genetic diseases, including cancer. However, the development of safe and efficient carriers for siRNA delivery still remains formidable hurdles for in vivo. The purpose of this study is to prepare siRNA-PLGA hybrid micelles to deliver the siRNA into the ovarian cancer cells and to evaluate of gene silencing effects in mice model. Here we focused on glypican-3 (Gpc3) gene silencing, which involved in tumor progression and inflammatory reaction, as a siRNA target in a murine ovarian cancer cells, HM-1. As a result, linear polyethyleneimine (LPEI)-coated siRNA-PLGA hybrid micelles were shown to effectively inhibit GPC3 expression in vitro in HM-1 cells, compared with siRNA in solution, because of their superior intracellular uptake and enhanced gene silencing effects. In addition, intraperitoneal administration of the cationic LPEI-coated siRNA-PLGA hybrid micelles decreased the number of tumor nodes in the mesentery, compared with the siRNA sole solution, in a HM-1 peritoneal dissemination model. These results suggested that siRNA-PLGA hybrid micelles could be an effective siRNA delivery tool in a murine ovarian cancer model, especially in case it targets molecules, such as Gpc3.

Deng H, Shang W, Lu G, et al.
Targeted and Multifunctional Technology for Identification between Hepatocellular Carcinoma and Liver Cirrhosis.
ACS Appl Mater Interfaces. 2019; 11(16):14526-14537 [PubMed] Related Publications
Continuously updated diagnostic methods and advanced imaging methods have led to an increase in the early detection rate of small liver cancer; however, even with current diagnosis methods, it is still challenging to accurately judge a nodule with a diameter less than 2 cm whether it is hepatocellular carcinoma or liver cirrhosis. To solve this issue, a new technology is needed to distinguish above two kinds of liver nodules. There is an emerging imaging method that improves tissue resolution and sensitivity to detect micronodules with diameters less than 2 cm. To detect micronodules, photoacoustic imaging was used to provide noninvasive images at depths of several centimeters with a resolution of approximately 100 μm. To improve specificity, we developed a probe that specifically targets hepatocellular carcinoma by recognizing the biomarker GPC3 on the hepatocellular carcinoma cell membrane. The probe not only has a strong photoacoustic signal but also has a magnetic resonance signal. Furthermore, the material owns photothermal effect that absorbs longer wavelength light and releases heat that effectively and accurately kills tumor cells, thus improving patient's survival and postoperative quality of life. Herein, we present a new technology that uses photoacoustic imaging to image and target microhepatocellular carcinoma biological processes derived from liver cirrhosis with high spatial resolution.

Kawaida M, Yamazaki K, Tsujikawa H, et al.
Diffuse and canalicular patterns of glypican-3 expression reflect malignancy of hepatocellular carcinoma.
Pathol Int. 2019; 69(3):125-134 [PubMed] Related Publications
Glypican-3 (GPC3) is expressed in most hepatocellular carcinomas (HCCs). To investigate the significance of various GPC3 staining patterns in HCC, we classified 134 HCC patients into three groups: those with diffuse GPC3 staining, canalicular GPC3 staining, and others (including negative staining). HCCs with diffuse staining were correlated with poor differentiation, high Ki-67 indices, high serum α-fetoprotein (AFP) levels, and early recurrence. In contrast, HCCs with canalicular staining were well differentiated with lower AFP levels. Overall survival in this group was better than that of the other two groups. Comparative analysis of GPC3 staining patterns with markers for HCC subclassification showed that diffuse staining was correlated with the expression of biliary/stem cell markers, whereas canalicular staining was correlated with expression of the markers of WNT-activated HCCs. Induction of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), known as a target of the WNT signaling pathway, in HCC cells resulted in reduced GPC3 expression in vitro. The LGR5-induced cells formed tumors with canaliculus-like structures in mice and showed canalicular GPC3 staining. The current findings showed the significance of recognizing distinct GPC3 staining patterns, i.e., diffuse and canalicular, which may reflect different carcinogenetic mechanisms and indicate the level of malignancy of HCC.

Chen D, Li Z, Zhu W, et al.
Stromal morphological changes and immunophenotypic features of precancerous lesions and hepatocellular carcinoma.
J Clin Pathol. 2019; 72(4):295-303 [PubMed] Related Publications
AIMS: To evaluate stromal histopathological features and immunostaining expression for differential diagnosis of low- and high-grade dysplastic nodules (HGDN) to early and progressed hepatocellular carcinomas (eHCC, pHCC).
MATERIALS: We evaluated sinusoid capillarisation (SC), solitary artery (SA), ductular reaction (DR), stromal invasion and expression of six biomarkers (GPC3, HSP70, GS, CD34, CK19, EpCAM) in a series of 97 cases.
RESULTS: Stromal morphological changes, including SC, DR and SA, exhibited significant differences in differential diagnosis. In one indicator, SC had the best sensitivity (90.00%) and accuracy (85.42%), and SA had the best specificity at 88.89 %. In combinations, SC +and SA +were favourable and optimal. The immunoreactivity of GPC3, HSP70 and GS increased significantly in line with the stepwise progression of hepatocarcinogenesis.
CONCLUSIONS: Stromal histopathology features are useful for diagnosing HGDN, eHCC and small HCC. The immunostaining panel of GPC3, HSP70 and GS can also be supplementary.

Chen D, Li Z, Song Q, et al.
Clinicopathological features and differential diagnosis of hepatocellular carcinoma in extrahepatic metastases.
Medicine (Baltimore). 2018; 97(50):e13356 [PubMed] Free Access to Full Article Related Publications
Extrahepatic metastasis of hepatocellular carcinoma (HCC) may cause a diagnostic problem. All 195 cases of histologic and immunostained sections were reviewed retrospectively in one center. The expression of arginase-1 (Arg-1), hepatocyte paraffin-1 (HepPar-1), glypican-3 (GPC-3), and α-Fetoprotein (AFP) was evaluated. Eighty cases of metastatic tumors of the liver were also collected to verify their effectiveness. Totally 151 cases had previous history of HCC, in whom 49 had history of liver transplantation. Forty-four cases were diagnosed as metastatic HCC at initial presentation. The most common extrahepatic metastatic sites were bone (57%), followed by lung, lymph node, etc. Around 19 cases were positive for 1 marker, 22 were positive for 2 markers, 95 were positive for 3 markers, and 59 were positive for 4 markers. With the number of antibody increased in the panel, the negative cases decreased. The sensitivity of ARG, GPC-3, HepPar-1, and AFP was 82.6%, 89.2%, 83.6% and 53.8%, and the specificity was 98.3%, 94.8%, 96.2% and 100%, respectively. These data suggest that the panel of ARG-1, GPC-3, HepPar-1 and AFP has a high sensitivity and specificity to differentiate HCC from non-HCC. This study indicated that HCC should be considered when diagnosing metastasis of unclear origin. It is recommended to use the panel of ARG-1, GPC-3, HepPar-1 and AFP to differentiate HCC from non-HCC in extrahepatic metastasis, because of their sensitivity and specificity, especially in poorly differentiated lesions.

Wang M, Tang Y, Chen Y, et al.
Catalytic hairpin assembly-programmed formation of clickable nucleic acids for electrochemical detection of liver cancer related short gene.
Anal Chim Acta. 2019; 1045:77-84 [PubMed] Related Publications
DNA amplification usually takes place in an aqueous system to facilitate a highly efficient reaction. Therefore, it is a challenge to connect the DNA amplification with popular dry chemical methods, whose signal outputs usually come from a solid-liquid interface. Here, by linking catalytic hairpin assembly (CHA) with electrochemical biosensors through clickable nucleic acids, we develop a facile method for the detection of liver cancer related short gene MXR7. On one hand, the method maintains the advantages of CHA especially its high efficiency by performing the whole process of CHA in aqueous phase. On the other hand, the method realizes electrochemical detection of MXR7 by transferring a clickable double-helix production of MXR7-triggerd CHA to a dibenzocyclooctyne-functionalized electrode quickly through copper-free click chemistry. In comparison with traditional biotin-streptavidin or hybridization-assisted conjugation, the click chemistry allows quick response in a quarter of an hour, shortening the detection time greatly. In addition, owing to the lower steric hindrance as compared with streptavidin, the signal intensity is strong, making a sensitive detection possible. The detection limit reaches 125 fM, better than previous electrochemical methods. Results also reveal that CHA in solution has much better efficiency than that on interface, allowing two orders of magnitude improvement in detection limit (125 fM vs. 50 pM) with a shorter detection time (135 min vs. 165 min). This work also provides a novel concept to connect aqueous amplification system with interfacial detection method for other bio-analysis.

Zhang Q, Han Z, Tao J, et al.
An innovative peptide with high affinity to GPC3 for hepatocellular carcinoma diagnosis.
Biomater Sci. 2018; 7(1):159-167 [PubMed] Related Publications
Glypican-3 (GPC3) is a key biomarker for early diagnosis of human hepatocellular carcinoma (HCC) due to its overexpression in most HCC tumor tissues. Recently, peptides with high affinity to GPC3 have attracted more attention because of their high biocompatibility, non-immunogenicity, fast clearing and easy modification. Herein, we have designed an innovative GPC3 targeting peptide (sequence: DYEMHLWWGTEL, denoted as IPA) by using structure-based virtual simulation. The higher binding abilities of IPA over the reported peptide (YP) were displayed on different cell lines, showing a positive correlation with GPC3 expressions, which were further verified by the GPC3 protein binding assay. The GPC3 targeting specificity of IPA was proved by peptide blocking and siRNA experiment. The localized anchor of peptide IPA on the cell membranes of HepG2 and Huh-7 with GPC3 overexpression confirmed the GPC3 binding capacity. By connecting a near-infrared dye MPA, the in vivo identification ability of IPA to GPC3 was also demonstrated on GPC3-positive (HepG2) and GPC3-negative (U87) xenograft-bearing mice. These results indicated that the designed IPA presented desirable GPC3 targeting ability, showing promising prospects in detecting the expression of GPC3 for HCC targeting imaging.

Zhang Y, Xu J, Zhang S, et al.
HOXA-AS2 Promotes Proliferation and Induces Epithelial-Mesenchymal Transition via the miR-520c-3p/GPC3 Axis in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2018; 50(6):2124-2138 [PubMed] Related Publications
BACKGROUND/AIMS: Previous studies have demonstrated that long non-coding RNAs (lncRNAs) may play critical roles in cancer biology, including Hepatocellular carcinoma (HCC). The HOXA cluster antisense RNA2 (HOXA-AS2) lncRNA plays an important role in carcinogenesis, however, the underlying role of HOXA-AS2 in HCC remains unknown. The present study examined the effects of HOXA-AS2 on the progression of HCC, and explored the underlying molecular mechanisms.
METHODS: Quantitative real-time PCR was used to detect HOXA-AS2 expression in HCC tissues and cell lines. Furthermore, the effects of HOXA-AS2 silencing and overexpression on cell proliferation, cell cycle, apoptosis, migration, and invasion were assessed in HCC in vitro and in vivo. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in HCC cells.
RESULTS: We observed that HOXA-AS2 was up-regulated in HCC tissues and cell lines. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited HCC cells proliferation by causing G1 arrest and promoting apoptosis, whereas HOXA-AS2 overexpression promoted cell growth. Further functional assays indicated that HOXA-AS2 significantly promoted HCC cell migration and invasion by promoting EMT. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in HCC cells. MiR-520c-3p was down-regulated and inversely correlated with HOXA-AS2 expression in HCC tissues. miR-520c-3p suppressed cell proliferation, invasion and migration in HCC cells, and enforced expression of miR-520c-3p attenuated the oncogenic effects of HOXA-AS2 in HCC cells. By bioinformatic analysis and dual-luciferase reporter assay, we found that miR-223-3p directly targeted the 3'-untranslated region (UTR) of Glypican-3 (GPC3), one of the key players in HCC. GPC3 was up-regulated in HCC tissues, and was negatively correlated with miR-520c-3p expression and positively correlated with HOXA-AS2 expression.
CONCLUSION: In summary, our results suggested that the HOXA-AS2/miR-520c-3p/GPC3 axis may play an important role in the regulation of PTC progression, which could serve as a biomarker and therapeutic target for HCC.

Li N, Gao W, Zhang YF, Ho M
Glypicans as Cancer Therapeutic Targets.
Trends Cancer. 2018; 4(11):741-754 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Glypicans are a group of cell-surface glycoproteins in which heparan sulfate (HS) glycosaminoglycan chains are covalently linked to a protein core. The glypican gene family is broadly conserved across animal species and plays important roles in biological processes. Glypicans can function as coreceptors for multiple signaling molecules known for regulating cell growth, motility, and differentiation. Some members of the glypican family, including glypican 2 (GPC2) and glypican 3 (GPC3), are expressed in childhood cancers and liver cancers, respectively. Antibody-based therapies targeting glypicans are being investigated in preclinical and clinical studies, with the goal of treating solid tumors that do not respond to standard therapies. These studies may establish glypicans as a new class of therapeutic targets for treating cancer.

Lorente L
New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma.
World J Gastroenterol. 2018; 24(37):4230-4242 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.

Tanaka Y, Tateishi R, Koike K
Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma.
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Proteoglycans, which consist of a protein core and glycosaminoglycan chains, are major components of the extracellular matrix and play physiological roles in maintaining tissue homeostasis. In the carcinogenic tissue microenvironment, proteoglycan expression changes dramatically. Altered proteoglycan expression on tumor and stromal cells affects cancer cell signaling pathways, which alters growth, migration, and angiogenesis and could facilitate tumorigenesis. This dysregulation of proteoglycans has been implicated in the pathogenesis of diseases such as hepatocellular carcinoma (HCC) and the underlying mechanism has been studied extensively. This review summarizes the current knowledge of the roles of proteoglycans in the genesis and progression of HCC. It focuses on well-investigated proteoglycans such as serglycin, syndecan-1, glypican 3, agrin, collagen XVIII/endostatin, versican, and decorin, with particular emphasis on the potential of these factors as biomarkers and therapeutic targets in HCC regarding the future perspective of precision medicine toward the "cure of HCC".

Li W, Xiao X, Li X, et al.
Detecting GPC3-Expressing Hepatocellular Carcinoma with L5 Peptide-Guided Pretargeting Approach: In Vitro and In Vivo MR Imaging Experiments.
Contrast Media Mol Imaging. 2018; 2018:9169072 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Objective: To investigate the potential of L5 peptide-guided pretargeting approach to identify GPC3-expressing hepatocellular carcinoma (HCC) using ultrasmall superparamagnetic iron oxide (USPIO) as the MR probe.
Methods: Immunofluorescence with carboxyfluorescein- (FAM-) labeled L5 peptide was performed in HepG2 cells. Polyethylene glycol-modified USPIO (PEG-USPIO) and its conjugation with streptavidin (SA-PEG-USPIO) were synthesized, and their hydrodynamic diameters, zeta potential, T
Results: The high specificity of L5 peptide for GPC3 was demonstrated. Generation of SA-PEG-USPIO nanoparticles with good biocompatibility (an average hydrodynamic diameter of 35.97 nm and a zeta potential of -7.91 mV), superparamagnetism (
Conclusion: L5 peptide-guided, two-step pretargeting approach with USPIO as the MR imaging probe is a lucrative strategy to specifically identify GPC3-expressing HCC.

Fernández D, Guereño M, Lago Huvelle MA, et al.
Signaling network involved in the GPC3-induced inhibition of breast cancer progression: role of canonical Wnt pathway.
J Cancer Res Clin Oncol. 2018; 144(12):2399-2418 [PubMed] Related Publications
PURPOSE: We have shown that GPC3 overexpression in breast cancer cells inhibits in vivo tumor progression, by acting as a metastatic suppressor. GPC3-overexpressing cells are less clonogenic, viable and motile, while their homotypic adhesion is increased. We have presented evidences indicating that GPC3 inhibits canonical Wnt and Akt pathways, while non-canonical Wnt and p38MAPK cascades are activated. In this study, we aimed to investigate whether GPC3-induced Wnt signaling inhibition modulates breast cancer cell properties as well as to describe the interactions among pathways modulated by GPC3.
METHODS: Fluorescence microscopy, qRT-PCR microarray, gene reporter assay and Western blotting were performed to determine gene expression levels, signaling pathway activities and molecule localization. Lithium was employed to activate canonical Wnt pathway and treated LM3-GPC3 cell viability, migration, cytoskeleton organization and homotypic adhesion were assessed using MTS, wound healing, phalloidin staining and suspension growth assays, respectively.
RESULTS: We provide new data demonstrating that GPC3 blocks-also at a transcriptional level-both autocrine and paracrine canonical Wnt activities, and that this inhibition is required for GPC3 to modulate migration and homotypic adhesion. Our results indicate that GPC3 is secreted into the extracellular media, suggesting that secreted GPC3 competes with Wnt factors or interacts with them and thus prevents Wnt binding to Fz receptors. We also describe the complex network of interactions among GPC3-modulated signaling pathways.
CONCLUSION: GPC3 is operating through an intricate molecular signaling network. From the balance of these interactions, the inhibition of breast metastatic spread induced by GPC3 emerges.

Lipovšek D, Carvajal I, Allentoff AJ, et al.
Adnectin-drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors.
Protein Eng Des Sel. 2018; 31(5):159-171 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody-drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens-but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin-drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads. Due to their small size (10 kDa), renal filtration eliminates Adnectins from the bloodstream within minutes to hours, ensuring low exposure to normal tissues. We used an engineered cysteine to conjugate an Adnectin that binds Glypican-3, a membrane protein overexpressed in hepatocellular carcinoma, to a cytotoxic derivative of tubulysin, with the drug-to-Adnectin ratio of 1. We demonstrate specific, nanomolar binding of this Adnectin-drug conjugate to human and murine Glypican-3; its high thermostability; its localization to target-expressing tumor cells in vitro and in vivo, its fast clearance from normal tissues and its efficacy against Glypican-3-positive mouse xenograft models.

Zhao M, Sun L, Lai JZ, et al.
Expression of RNA-binding protein LIN28 in classic gastric hepatoid carcinomas, gastric fetal type gastrointestinal adenocarcinomas, and hepatocellular carcinomas: An immunohistochemical study with comparison to SALL4, alpha-fetoprotein, glypican-3, and Hep Par1.
Pathol Res Pract. 2018; 214(10):1707-1712 [PubMed] Related Publications
INTRODUCTION: Gastric hepatoid carcinomas (GHCs) include type I (classic) and type II (fetal type gastrointestinal adenocarcinoma). The classic type shows overlapping morphologic features with those of hepatocellular carcinoma (HCC). The aim of this study is to investigate expression of LIN28 in GHCs and explore its utility to distinguish classic GHC from HCC.
METHODS: We investigated immunohistochemical expression of LIN28 in 93 primary GHCs (47 type I, 46 type II) and 60 HCCs with comparison to SALL4, AFP, glypican-3, Hep Par1, p-CEA and CK7. We also stained LIN28 and SALL4 in 52 conventional gastric adenocarcinomas to assess their specificity in gastric carcinomas.
RESULTS: Classic GHCs and fetal type gastrointestinal adenocarcinomas showed positive LIN28 in 21/47 (45%) and 10/46 (22%), SALL4 in 41/47 (87%) and 36/46 (78%), AFP in 30/46 (65%) and 33/46 (72%), glypican-3 in 31/41 (76%) and 24/38 (63%), Hep Par1 in 27/41 (66%) and 28/37 (76%), and CK7 in 15/40 (38%) and 25/38 (66%), respectively. p-CEA staining was seen in 19/44 (43%) classic GHCs. Among HCCs, LIN28, SALL4, AFP, glypican-3, Hep Par1, p-CEA and CK7 was seen in 1/60 (2%), 0/60 (0%), 6/30 (20%), 23/30 (77%), 29/30 (97%), 28/30 (93%) and 21/30 (70%) cases, respectively. LIN28 and SALL4 staining was seen in 2/52 (4%) and 14/52 (27%) gastric conventional adenocarcinomas, respectively. The sensitivity and specificity of distinguishing classic GHCs from HCCs was 45% and 98% for LIN28, 87% and 100% for SALL4, 65% and 80% for AFP, 76% and 30% for glypican-3, 66% and 3% for Hep Par1, 43% and 7% for p-CEA, and 38% and 30% for CK7, respectively. Combining LIN28 and SALL4 increased the sensitivity to 96% with 98% specificity to distinguish classic GHCs from HCCs.
CONCLUSIONS: LIN28 is a very specific marker (98% specificity) for distinguishing classic GHCs from HCCs though it is not as sensitive as SALL4. AFP, glypican-3, Hep Par1 and p-CEA are not useful in distinguishing classic GHCs from HCCs. Combining LIN28 and SALL4 increased the sensitivity to distinguish classic PHCs from HCCs.

Jiang P, Gu L, Zhou Y, et al.
Synchronous Laryngeal Squamous Cell Carcinoma and Intrahepatic Cholangiocarcinoma Present in an Obese Male with Poor Prognosis.
Anticancer Res. 2018; 38(9):5547-5550 [PubMed] Related Publications
Concurrent laryngeal squamous cell carcinoma and intrahepatic cholangiocarcinoma is rare and no prior report has been found through a PubMed search. Here we report such a case of a 51-year old obese male presenting with hoarseness and trouble swallowing for 2 to 3 months. Imaging findings of computer tomography (CT) and magnetic resonance imaging (MRI) with and without contrast were suspicious for a T3N2 supraglottic laryngeal cancer. Laryngeal biopsy showed a well differentiated squamous cell carcinoma (SCC). As part of the evaluation of the laryngeal SCC, MRI abdomen showed an enhancing mass (4.6 cm in the greatest dimension) with diffusion restriction and capsular retraction in the right lobe of the liver. Ultrasound-guided percutaneous biopsy of the liver revealed a moderately differentiated adenocarcinoma, that was strongly and diffusely positive for CK7 and CK19, weakly positive for CDX2, and negative for HepPar 1, glypican 3, CK20, PSA and TTF1. The immunohistochemistry profile was consistent with cholangiocarcinoma. This is a unique case of laryngeal squamous cell carcinoma with concurrent cholangiocarcinoma. The prognosis was poor and the patient was placed in hospice care in two months after the diagnoses. To the best of our knowledge, this is the first documented case of synchronous laryngeal squamous cell carcinoma and intrahepatic cholangiocarcinoma. The pathogenesis, diagnosis and treatment of the diseases are discussed.

Zhao M, Liu Z, Dong L, et al.
A GPC3-specific aptamer-mediated magnetic resonance probe for hepatocellular carcinoma.
Int J Nanomedicine. 2018; 13:4433-4443 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Purpose: To construct and test a hepatocellular carcinoma (HCC)-targeted magnetic resonance probe based on a glypican-3 (GPC3)-specific aptamer (AP613-1) with ultrasmall superpara-magnetic iron oxide (USPIO).
Methods: Oleic acid-coated USPIO nanoparticles were modified with amino polyethylene glycol on the surface. Amino groups of the USPIO nanoparticles were reacted with the carboxyl group of 5' carboxyl-modified AP613-1, forming an aptamer-mediated USPIO (Apt-USPIO) probe. The material characterization of this probe including transmission electron microscopy (TEM), zeta potential, dynamic laser scattering, and magnetic behavior was carried out. The targeting efficiency and magnetic resonance imaging (MRI) performance of Apt-USPIO were evaluated both in vitro and in vivo with USPIO alone as a control. The cytotoxicity and bio-compatibility of Apt-USPIO and USPIO were analyzed by cell counting kit-8 tests in vitro and animal experiments in vivo.
Results: TEM imaging revealed that the Apt-USPIO nanoparticles were spherical in shape and well dispersed. Specific uptake of Apt-USPIO in Huh-7 cells could be observed using the Prussian blue staining test; however, no uptake of USPIO could be found. In vitro phantom T
Conclusion: In this study, a molecular MRI probe which was highly specific to GPC3 on HCC was successfully prepared. Our results validated the targeted imaging effect of this Apt-USPIO probe in vivo for GPC3-expressing HCCs in xenograft mice.

Pan Z, Di S, Shi B, et al.
Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein.
Cancer Immunol Immunother. 2018; 67(10):1621-1634 [PubMed] Related Publications
Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1-CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3

Yin LC, Luo ZC, Gao YX, et al.
Twist Expression in Circulating Hepatocellular Carcinoma Cells Predicts Metastasis and Prognoses.
Biomed Res Int. 2018; 2018:3789613 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Hepatocellular carcinoma (HCC) is one of the leading malignancies worldwide. Enumeration of circulating tumor cells (CTCs) has been demonstrated to be a prognostic indicator in HCC. Twist plays a critical role in metastasis and has been proposed as a biomarker for epithelial-mesenchymal transition (EMT). However, links between the expression of Twist in CTCs and HCC clinical parameters are still unclear. This study aims to evaluate the relationship between Twist expression in CTCs and clinicohistopathological risk factors of HCC. Between June 2015 and July 2017, 80 HCC patients and 10 healthy volunteers were enrolled in this study. CTCs were isolated and analyzed by the optimized CanPatrol™ CTC-enrichment technique. Our analysis showed that Twist+ CTCs were detected in 54 of the 80 (67.5%) HCC patients. The positive ratios of Twist+ CTCs correlated with portal vein tumor thrombi, TNM staging, AFP, cirrhosis, tumor number, tumor size, and microvascular invasion. Meanwhile, the follow-up results of the 33 HCC patients who underwent hepatectomy showed that the positive ratios of Twist+ CTCs were closely correlated with the rate of metastasis or recurrence and the mortality rate. The ROC curve analyses suggested that the prognostic evaluation of Twist+ CTCs outperforms CTCs alone. Twist+ CTCs showed higher expression in Glypican-3 protein. In conclusion, Twist expression in CTCs could serve as a biomarker for evaluating HCC metastasis and prognosis.

Miller EM, Tymon-Rosario J, Sunkara J, et al.
Comparative Use of Napsin A and Glypican 3 to Distinguish Endometrial Clear Cell from Serous and Endometrioid Carcinomas.
Int J Gynecol Cancer. 2018; 28(7):1318-1324 [PubMed] Related Publications
OBJECTIVE: Diagnosis of endometrial clear cell carcinomas is difficult owing to the low reproducibility of histological cell type in high-grade endometrial cancers. Recently, immunoreactivity for napsin A and glypican 3 has been reported in clear cell cancers. We sought to evaluate the use of napsin A and glypican 3 staining to distinguish clear cell carcinoma from other high-grade endometrial cancers.
METHODS/MATERIALS: Twenty cases of pure and mixed endometrial clear cell carcinoma were extracted from the 2000-2014 archival material in the Departments of Obstetrics & Gynecology and Pathology at Montefiore Medical Center and compared to serous and grade 3 endometrioid controls. Representative sections were stained with monoclonal antibodies to napsin A and glypican 3. Immunostains were independently reviewed by 2 pathologists to assess frequency and pattern of staining. Charts were reviewed for clinicopathologic and treatment data.
RESULTS: Granular cytoplasmic positivity for napsin A was observed in 70% of endometrial clear cell carcinomas; only 25% showed cytoplasmic or membranous glypican 3 positivity. No serous or high-grade endometrioid tumors stained for either marker. No cases of clear cell carcinoma that stained negative for napsin A stained positive for glypican 3. No difference in the immunohistochemical profile was found between pure and mixed clear cell carcinomas and between early- and advanced-stage clear cell carcinomas.
CONCLUSIONS: Napsin A is a more sensitive marker for endometrial clear cell carcinoma than glypican 3. In histologically ambiguous cases, napsin A and glypican 3 may help distinguish clear cell carcinoma from other high-grade histologies. Further investigation of endometrial clear cell carcinoma is needed to identify additional diagnostic tools for this rare histology. Correlation of a unique immunohistochemical profile and clinical outcomes is necessary.

Gan H, Chen L, Sui X, et al.
Enhanced delivery of sorafenib with anti-GPC3 antibody-conjugated TPGS-b-PCL/Pluronic P123 polymeric nanoparticles for targeted therapy of hepatocellular carcinoma.
Mater Sci Eng C Mater Biol Appl. 2018; 91:395-403 [PubMed] Related Publications
Although sorafenib (SFB) showed improved efficacy and much reduced the side effects in clinical liver cancer therapy, its therapeutic efficacy was still greatly limited due to short half-life in vivo as well as drug resistance. To solve these problems, we developed a novel SFB-loaded polymeric nanoparticle for targeted therapy of liver cancer. This polymeric nanoparticle, referred to NP-SFB-Ab, was fabricated from self-assembly of biodegradable block copolymers TPGS-b-poly(caprolactone) (TPGS-b-PCL) and Pluronic P123 and drug SFB, followed by conjugating the anti-GPC3 antibody. NP-SFB-Ab showed robust stability and achieve excellent SFB release in cell medium. The CLSM demonstrated that the Ab-conjugated NP exhibited much higher cellular uptake in HepG2 human liver cells than non-targeted NP. The MTT assay also confirmed that NP-SFB-Ab caused much greater cytotoxicity than non-targeted NP-SFB and free SFB. Finally, NP-SFB-Ab was proved to greatly inhibit the tumor growth of HepG2 xenograft-bearing nude mice without obvious side effects. Therefore, this NP-SFB-Ab provides a promising new approach for targeted therapy of hepatocellular carcinoma.

Hu P, Ke C, Guo X, et al.
Both glypican-3/Wnt/β-catenin signaling pathway and autophagy contributed to the inhibitory effect of curcumin on hepatocellular carcinoma.
Dig Liver Dis. 2019; 51(1):120-126 [PubMed] Related Publications
AIM: The aim of this study is to investigate the role of glypican-3(GPC3)/wnt/β-catenin signaling pathway and autophagy in the regulation of hepatocellular carcinoma (HCC) growth mediated by curcumin.
METHODS: HepG2 cells were treated with various concentrations of curcumin and/or GPC3-targeting siRNA in the presence or absence of 3-MA. Cell proliferation and apoptosis were determined by MTT and TUNEL assay, respectively. Expression of GPC3, β-catenin, c-myc, LC3, and Beclin1 was determined by western blotting. In addition, curcumin was tested in tumor xenografts mice model, Caliper IVIS Lumina II was used to monitor the tumor growth, and GPC3/wnt/β-catenin signaling proteins were determined by western blotting.
RESULTS: Curcumin treatment led to proliferation inhibition and apoptosis induction in HepG2 cells in a concentration-dependent manner, and suppressed HCC tumor growth in vivo. Further analysis showed that curcumin treatment inactivated Wnt/β-catenin signaling and decreased GPC3 expression, silencing of GPC3 expression promoted the effects of curcumin on Wnt/β-catenin signaling. In addition, inhibiting autophagy by 3-MA relieved curcumin-dependent down-regulation of GPC3.
CONCLUSION: Curcumin suppressed HCC tumor growth through down-regulating GPC3/wnt/β-catenin signaling pathway, which was partially mediated by activation of autophagy.

Yi P, Niu HL, Gao Q, et al.
[Pathologic features on gonadal changes of sexual developmental disorders in children].
Zhonghua Bing Li Xue Za Zhi. 2018; 47(7):531-535 [PubMed] Related Publications

Yang C, Sun L, Lai JZ, et al.
Primary Hepatoid Carcinoma of the Pancreas: A Clinicopathological Study of 3 Cases With Review of Additional 31 Cases in the Literature.
Int J Surg Pathol. 2019; 27(1):28-42 [PubMed] Related Publications
Primary pancreatic hepatoid carcinoma (PHC) is very rare. Here, we reported 3 such cases with review of additional 31 cases in the literature. Our 3 patients were male (83, 72, and 54 years old, respectively). Serum α-fetoprotein (AFP) was elevated in 1 patient (case 3, 8338 ng/mL) and not measured in the other two. The PHC in patient 1 (pathological stage pT2N0M0) and patient 2 (pT3N0M0) showed pure hepatocellular carcinoma (HCC)-like morphology, whereas in case 3 it was a PHC with true glandular differentiation (pT4N0M0). The diagnosis of PHC was confirmed with positive immunohistochemical staining in the tumor cells for AFP (2/3), Hep Par 1 (3/3), glypican-3 (2/3), arginase-1 (2/3), and Sal-like protein 4 (1/3). CD10 and polyclonal carcinoembryonic antigen stains show focal canalicular pattern in 2/3 tumors. Patient 1 did not receive further treatment after resection and was alive with no evidence of disease at 107 months. Patient 2 died of postoperative complications, whereas patient 3 received postsurgical chemoradiation and died of disease at 29 months. Our findings and literature review indicate that PHCs can be divided into 4 histological subtypes: with pure HCC-like morphology (n = 22), with neuroendocrine differentiation (n = 8), with true glandular differentiation (n = 3), and with acinar cell differentiation (n = 1). On univariate analysis, pure HCC-like morphology was associated with better disease-specific survival (DSS; P = .04), whereas lymph node and distant metastases were associated with worse DSS ( P = .002 for both). Age, gender, presenting symptoms, serum AFP level, and T stage were not associated with DSS. On multivariate analysis, none of these parameters was significantly associated with DSS.

Moek KL, Fehrmann RSN, van der Vegt B, et al.
Glypican 3 Overexpression across a Broad Spectrum of Tumor Types Discovered with Functional Genomic mRNA Profiling of a Large Cancer Database.
Am J Pathol. 2018; 188(9):1973-1981 [PubMed] Related Publications
Glypican 3 (GPC3), a membrane-bound heparan sulfate proteoglycan, is overexpressed in approximately 70% to 80% of hepatocellular carcinomas, but is not expressed commonly in healthy tissues. This raised interest in GPC3 as a drug target and several GPC3-targeting drugs are in clinical development. We therefore predicted GPC3 protein overexpression across tumors and validated these predictions. Functional genomic mRNA profiling was applied to the expression profiles of 18,055 patient-derived tumor samples to predict GPC3 overexpression at the protein level in 60 tumor types and subtypes using healthy tissues as reference. For validation, predictions were compared with immunohistochemical (IHC) staining of a breast cancer tissue microarray and literature data reporting IHC GPC3 overexpression in various solid, hematologic, and pediatric tumors. The percentage of samples with predicted GPC3 overexpression was 77% for hepatocellular carcinomas (n = 364), 45% for squamous cell lung cancers (n = 405), and 19% for head and neck squamous cell cancers (n = 344). Breast cancer tissue microarray analysis showed GPC3 expression ranged from 12% to 17% in subgroups based on estrogen receptor and human epidermal growth factor receptor 2 status. In 28 of 34 tumor types for which functional genomic mRNA data could be compared with IHC there was a relative difference of ≤10%. This study provides a data-driven prioritization of tumor types and subtypes for future research with GPC3-targeting therapies.

Chao WT, Liu CH, Lai CR, et al.
Alpha-fetoprotein-producing ovarian clear cell adenocarcinoma with fetal gut differentiation: a rare case report and literature review.
J Ovarian Res. 2018; 11(1):52 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Alpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed.
CASE PRESENTATION: We report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review.
CONCLUSIONS: A total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Han HH, Qiu YJ, Shi YY, et al.
Glypican-3-targeted precision diagnosis of hepatocellular carcinoma on clinical sections with a supramolecular 2D imaging probe.
Theranostics. 2018; 8(12):3268-3274 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The ability of chemical tools to effectively detect malignancy in frozen sections removed from patients during surgery is important for the timely determination of the subsequent surgical program. However, current clinical methods for tissue imaging rely on dye-based staining or antibody-based techniques, which are sluggish and complicated.

Tang X, Chen L, Li A, et al.
Anti-GPC3 antibody-modified sorafenib-loaded nanoparticles significantly inhibited HepG2 hepatocellular carcinoma.
Drug Deliv. 2018; 25(1):1484-1494 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Sorafenib (SFB) has improved the treatment of hepatocellular carcinoma (HCC) and has fewer severe side effects than other agents used for that purpose. However, due to a lack of tumor-specific targeting, the concentration of the drug in tumor tissue cannot be permanently maintained at a level that inhibits tumor growth. To overcome this problem, we developed a novel SFB-loaded polymer nanoparticle (NP). The NP (a TPGS-b-PCL copolymer that was synthesized from ε-caprolactone and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via ring-opening polymerization) contains Pluronic P123 and SFB, and its surface is modified with anti-GPC3 antibody to produce the polymer nanoparticle (NP-SFB-Ab). The Ab-conjugated NPs had higher cellular uptake by HepG2 cells than did non-antibody-conjugated SPD-containing nanoparticles (NP-SFB). The NP-SFB-Ab also displayed better stability characteristics, released higher levels of SFB into cell culture medium, and was more cytotoxic to tumor cells than was non-targeted NP-SFB and free SFB. The NP-SFB-Ab downregulated expression of the anti-apoptosis molecule MCL-1, which led to polymerization of Bax and Bak in mitochondrial cytosol. The NP-SFB-AB also promoted the mitochondrial release of cytochrome C, resulting in cellular apoptosis. Moreover, the NP-SFB-Ab significantly inhibited the growth of HepG2 xenograft tumors in nude mice without producing obvious side effects. These findings suggest that NP-SFB-Ab is a promising new method for achieving targeted therapy of HCC.

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