Gene Summary

Gene:PIGS; phosphatidylinositol glycan anchor biosynthesis class S
Aliases: GPIBD18
Summary:This gene encodes a protein that is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI) anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:GPI transamidase component PIG-S
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (8)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

  • Cell Line
  • Sequence Alignment
  • DNA
  • Cell Proliferation
  • Cattle
  • Genotype
  • Cloning, Molecular
  • Molecular Sequence Data
  • Swine
  • Apoptosis
  • Liver Cancer
  • Mutation
  • Kidney
  • Transcription Factors
  • Immunohistochemistry
  • Genetic Therapy
  • Lung Cancer
  • Messenger RNA
  • Breast Cancer
  • Amino Acid Sequence
  • Phenotype
  • Guinea Pigs
  • Pancreatic Cancer
  • Neoplasm Proteins
  • Melanoma
  • Neoplastic Cell Transformation
  • Genetic Predisposition
  • Signal Transduction
  • Thyroid Cancer
  • alpha-Glucosidases
  • Cancer Gene Expression Regulation
  • Chromosome 17
  • Sequence Homology
  • Polymerase Chain Reaction
  • Disease Models, Animal
  • Base Sequence
  • Tumor Suppressor Gene
  • Species Specificity
  • Cultured Cells
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: PIGS (cancer-related)

Dybicz M, Borkowski PK, Jonas M, et al.
First Report of
Biomed Res Int. 2019; 2019:2474839 [PubMed] Free Access to Full Article Related Publications
Cystic echinococcosis is considered as an emerging zoonosis that can develop asymptomatically for years, clinically nonpathognomic. The disease is of public health importance due to often late, difficult diagnostics, uncertain results of treatment, the need to remove hydatid cysts surgically in advanced cases, and poor prognosis in untreated patients. Six Polish female patients with diagnosed cystic echinococcosis (CE) were examined. DNA extracted from the liver and lung samples served for amplification of mitochondrial

Lee D, Kim KH, Lee WY, et al.
Multiple Targets of 3-Dehydroxyceanothetric Acid 2-Methyl Ester to Protect Against Cisplatin-Induced Cytotoxicity in Kidney Epithelial LLC-PK1 Cells.
Molecules. 2019; 24(5) [PubMed] Free Access to Full Article Related Publications
Chronic exposure to cisplatin, a potent anticancer drug, causes irreversible kidney damage. In this study, we investigated the protective effect and mechanism of nine lupane- and ceanothane-type triterpenoids isolated from jujube (

Loyez M, Larrieu JC, Chevineau S, et al.
In situ cancer diagnosis through online plasmonics.
Biosens Bioelectron. 2019; 131:104-112 [PubMed] Related Publications
Most cancer diagnoses rely on biomarkers detection. This could be improved if directly conducted in suspicious cancer spots, preventing the need for biopsy. Lung cancer remains a perfect study-case for such a development, as it is generally detected at advanced stage and is in the need for early diagnosis techniques. To this aim, we have designed a minimally invasive catheter-embedded biosensor. It combines a specific grating structure photo-imprinted in a telecommunication-grade optical fiber and an overlay made of a thin metal coating on which receptors are grafted, yielding plasmonic coupling. Our optrode targets a type of cytokeratins, overexpressed at the surface of cancer cells. It was assayed ex vivo in resected lung tissues collected from a dozen of patients. Biosensing responses were confirmed by immunohistochemistry, conducted on the same samples. In addition to accurate biosensing, our gratings inherently enable force-sensing features, which also allow a fine positioning of the probe in the tissue. Finally, the in vivo navigation of the bronchoscope-embedded sensor was validated into pig lungs. These achievements are a critical milestone towards the development of this micro/nano biosensor as a cost-effective and weakly invasive diagnostic tool for applications in areas of critical access such as brain, liver or prostate.

Bez M, Foiret J, Shapiro G, et al.
Nonviral ultrasound-mediated gene delivery in small and large animal models.
Nat Protoc. 2019; 14(4):1015-1026 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Ultrasound-mediated gene delivery (sonoporation) is a minimally invasive, nonviral and clinically translatable method of gene therapy. This method offers a favorable safety profile over that of viral vectors and is less invasive as compared with other physical gene delivery approaches (e.g., electroporation). We have previously used sonoporation to overexpress transgenes in different skeletal tissues in order to induce tissue regeneration. Here, we provide a protocol that could easily be adapted to address various other targets of tissue regeneration or additional applications, such as cancer and neurodegenerative diseases. This protocol describes how to prepare, conduct and optimize ultrasound-mediated gene delivery in both a murine and a porcine animal model. The protocol includes the preparation of a microbubble-DNA mix and in vivo sonoporation under ultrasound imaging. Ultrasound-mediated gene delivery can be accomplished within 10 min. After DNA delivery, animals can be followed to monitor gene expression, protein secretion and other transgene-specific outcomes, including tissue regeneration. This procedure can be accomplished by a competent graduate student or technician with prior experience in ultrasound imaging or in performing in vivo procedures.

Zhu Y, Zhou C, He Q
High miR-139-3p expression predicts a better prognosis for hepatocellular carcinoma: a pooled analysis.
J Int Med Res. 2019; 47(1):383-390 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
OBJECTIVE: To observe the expression and clinical significance of micro RNA (miR)-139-3p in liver cancer tissues, and to explore its relationship with miR-139-3p target genes related to the prognosis of hepatocellular carcinoma (HCC).
METHODS: A total of 362 patients with HCC were included in the study. Liver hepatocellular carcinoma data were obtained directly from The Cancer Genome Atlas data portal .The bioinformatics analysis tool TargetScan was applied to predict miR-139-3p target genes.
RESULTS: Survival time was significantly higher in patients with high miR-139-3p expression, compared with the low miR-139-3p expression group. Bioinformatics analysis showed that miR-139-3p target genes ISG20L2, RAD54B, KIAA0101, and PIGS were significantly negatively correlated with miR-139-3p expression.
CONCLUSIONS: High miR-139-3p expression in HCC tissues was indicative of good patient prognosis. miR-139-3p target genes ISG20L2, RAD54B, KIAA0101, and PIGS were related to HCC prognosis.

Saldin LT, Patel S, Zhang L, et al.
Extracellular Matrix Degradation Products Downregulate Neoplastic Esophageal Cell Phenotype.
Tissue Eng Part A. 2019; 25(5-6):487-498 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
IMPACT STATEMENT: Extracellular matrix (ECM) biomaterials were used to treat esophageal cancer patients after cancer resection and promoted regrowth of normal mucosa without recurrence of cancer. The present study investigates the mechanisms by which these materials were successful to prevent the cancerous phenotype. ECM downregulated neoplastic esophageal cell function (proliferation, metabolism), but normal esophageal epithelial cells were unaffected

Mochimaru Y, Negishi J, Murakami S, et al.
Metals Differentially Activate Ovarian Cancer G Protein-Coupled Receptor 1 in Various Species.
Zoolog Sci. 2018; 35(2):109-114 [PubMed] Related Publications
Human, mouse, and zebrafish ovarian cancer G protein-coupled receptors (OGR1s) are activated by both metals and extracellular protons. In the present study, we examined whether pig, rat, chicken, and Xenopus OGR1 homologs could sense and be activated by protons and metals. We found that all homologs stimulated serum response element (SRE)-driven promoter activities when they are stimulated by protons. On the other hand, metals differentially activated the homologs. The results using chimeric receptors of human and zebrafish OGR1s indicate that the specificity of the metal-induced activation lies in the extracellular region. These results suggest that protons are an evolutionally conserved agonist of OGR1. However, the types of metals that activated the receptor differed among the homologs.

Cao X, Nie X, Xiong S, et al.
Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity.
Redox Biol. 2018; 15:513-521 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Cisplatin is a major chemotherapeutic drug for solid tumors whereas it may lead to severe nephrotoxicity. Despite decades of efforts, effective therapies remain largely lacking for this disease. In the current research, we investigated the therapeutic effect of hydrogen polysulfide, a novel hydrogen sulfide (H

Wang K, Jin Q, Ruan D, et al.
Cre-dependent Cas9-expressing pigs enable efficient in vivo genome editing.
Genome Res. 2017; 27(12):2061-2071 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Despite being time-consuming and costly, generating genome-edited pigs holds great promise for agricultural, biomedical, and pharmaceutical applications. To further facilitate genome editing in pigs, we report here establishment of a pig line with Cre-inducible Cas9 expression that allows a variety of ex vivo genome editing in fibroblast cells including single- and multigene modifications, chromosome rearrangements, and efficient in vivo genetic modifications. As a proof of principle, we were able to simultaneously inactivate five tumor suppressor genes (

Putthanachote N, Promthet S, Hurst C, et al.
The XRCC 1 DNA repair gene modifies the environmental risk of stomach cancer: a hospital-based matched case-control study.
BMC Cancer. 2017; 17(1):680 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Previous studies have found that polymorphisms of the DNA repair gene X-ray repair cross-complementing group 1(XRCC1) and environmental factors are both associated with an increased risk of stomach cancer, but no study has reported on the potential additive effect of these factors among Thai people. The aim of this study was to investigate whether the risk of stomach cancer from XRCC1 gene polymorphisms was modified by environmental factors in the Thai population.
METHODS: Hospital-based matched case-control study data were collected from 101 new stomach cancer cases and 202 controls, which were recruited from2002 to 2006 and were matched for gender and age. Genotype analysis was performed using real-time PCR-HRM. The data were analysed by the chi-square test and conditional logistic regression.
RESULTS: The Arg/Arg homozygote polymorphism of the XRCC1 gene was associated with an increased risk of stomach cancer in the Thai population (OR
CONCLUSIONS: The effect of the XRCC1 gene homozygosity, particularly Arg/Arg, on the risk for stomach cancer was elevated by a high intake of vegetable oils and salt.

Meyerholz DK, Ofori-Amanfo GK, Leidinger MR, et al.
Immunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine Models.
J Histochem Cytochem. 2017; 65(10):607-618 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Neurofibromatosis type 1 (NF1) is a common, cancer-predisposing disease caused by mutations in the NF1 tumor gene. Patients with NF1 have an increased risk for benign and malignant tumors of the nervous system (e.g., neurofibromas, malignant peripheral nerve sheath tumors, gliomas) and other tissues (e.g., leukemias, rhabdomyosarcoma, etc.) as well as increased susceptibility to learning disabilities, chronic pain/migraines, hypertension, pigmentary changes, and developmental lesions (e.g., tibial pseudoarthrosis). Pigs are an attractive and upcoming animal model for future NF1 studies, but a potential limitation to porcine model research has been the lack of validated reagents for direct translational study to humans. To address that issue, we used formalin-fixed tissues (human and pigs) to evaluate select immunohistochemical markers (activated caspase-3, allograft inflammatory factor-1, beta-tubulin III, calbindin D, CD13, CD20, desmin, epithelial membrane antigen, glial fibrillary acidic protein, glucose transporter-1, laminin, myelin basic protein, myoglobin, proliferating cell nuclear antigen, S100, vimentin, and von Willebrand factor). The markers were validated by comparing known expression and localization in human and pig tissues. Validation of these markers on fixed tissues will facilitate prospective immunohistochemical studies of NF1 pigs, as well as other pig models, in a more efficient, reproducible, and translationally relevant manner.

Xing T, Camacho Salazar R, Chen YH
Animal models for studying epithelial barriers in neonatal necrotizing enterocolitis, inflammatory bowel disease and colorectal cancer.
Tissue Barriers. 2017; 5(4):e1356901 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The intestinal epithelial cells line the luminal surface of the entire gastrointestinal tract which is crucial for the absorption of nutrients and prevention of pathogens entering from the external environment. The epithelial barrier plays an important role in organ development, disease pathogenesis, and aging. The major component of an epithelial barrier is the single columnar epithelium and tight junctions. Tight junctions are located at the most apical region of the junctional complex and contain many integral membrane proteins, such as occludin, the claudin family, and junctional adhesion molecules (JAMs). The disruption of intestinal epithelial barriers may lead to several pathophysiological conditions causing malabsorption of nutrition and chronic inflammation. In this review, we provide an update on the alterations of epithelial barriers associated with gut diseases using experimental animal models; we appraise the role of tight junctions in neonatal necrotizing enterocolitis (NEC), inflammatory bowel disease (IBD), and colorectal cancer; we also compare some common features as well as differences and similarities in the pathophysiology of intestinal inflammation in neonatal (NEC) and adult (IBD) gut.

Kawasaki J, Kawamura M, Ohsato Y, et al.
Presence of a Shared 5'-Leader Sequence in Ancestral Human and Mammalian Retroviruses and Its Transduction into Feline Leukemia Virus.
J Virol. 2017; 91(20) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Recombination events induce significant genetic changes, and this process can result in virus genetic diversity or in the generation of novel pathogenicity. We discovered a new recombinant feline leukemia virus (FeLV)

Dwight T, Na U, Kim E, et al.
Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma.
BMC Cancer. 2017; 17(1):497 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH.
METHODS: DNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293).
RESULTS: Using massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant.
CONCLUSIONS: Our studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.

Berthelsen MF, Callesen MM, Østergaard TS, et al.
Pancreas specific expression of oncogenes in a porcine model.
Transgenic Res. 2017; 26(5):603-612 [PubMed] Related Publications
Pancreatic cancer is the fourth leading course of cancer death and early detection of the disease is crucial for successful treatment. However, pancreatic cancer is difficult to detect in its earliest stages and once symptoms appear, the cancer has often progressed beyond possibility for curing. Research into the disease has been hampered by the lack of good models. We have generated a porcine model of pancreatic cancer with use of transgenic overexpression of an oncogene cassette containing MYC, KRAS

Schachtschneider KM, Liu Y, Mäkeläinen S, et al.
Oncopig Soft-Tissue Sarcomas Recapitulate Key Transcriptional Features of Human Sarcomas.
Sci Rep. 2017; 7(1):2624 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Human soft-tissue sarcomas (STS) are rare mesenchymal tumors with a 5-year survival rate of 50%, highlighting the need for further STS research. Research has been hampered by limited human sarcoma cell line availability and the large number of STS subtypes, making development of STS cell lines and animal models representative of the diverse human STS subtypes critical. Pigs represent ideal human disease models due to their similar size, anatomy, metabolism, and genetics compared to humans. The Oncopig encodes inducible KRAS

Lechanteur A, Furst T, Evrard B, et al.
Promoting Vaginal Distribution of E7 and MCL-1 siRNA-Silencing Nanoparticles for Cervical Cancer Treatment.
Mol Pharm. 2017; 14(5):1706-1717 [PubMed] Related Publications
There is an urgent need to develop a less aggressive and more effective treatment against cervical lesions induced by different high-risk human papillomavirus (HR-HPV). We investigated the potential of a cocktail of small interfering RNA (siRNA) directed against the oncoprotein E6 (E6), the oncoprotein E7 (E7), or the antiapoptotic protein MCL-1 (MCL-1). The combination of siRNA anti-E7 and anti-MCL-1 demonstrated high efficacy on multiple HPV16 and HPV18 cell lines and no effects on healthy keratinocytes. This gene therapy has been considered for a vaginal administration since this route of application holds high potential for the treatment of diseases in the female reproductive tracts. Therefore, PEGylated lipoplexes have been designed and characterized to protect siRNA and to diffuse in the mucosal environment before they reach the cervico/vaginal epithelium. This new nanovector complexed to the combination of active siRNA induced an efficient mRNA knockdown since biological effects were obtained in vitro. This work also provided evidence that the PEGylated lipoplexes had appropriate physicochemical properties to diffuse into a mucin network according to size measurement experiments in artificial mucus. After demonstrating the distribution and the efficacy of siRNA into a 3D-cervical model lesion and through porcine vaginal mucosa, in vivo experiments in mouse have been performed under physiological conditions. This study revealed a complete and sustained coverage of the mucosal epithelium following an unique vaginal administration of fluorescent PEGylated lipoplexes. Overall, our results showed the potential of the PEGylated lipoplexes for the prolonged delivery of active siRNA to treat HPV-induced lesions.

Choi YJ, Park JH, Han JW, et al.
Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells.
Int J Mol Sci. 2016; 17(12) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The cancer stem cell (CSC) hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs) have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs). In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells) and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH) and CD133 by fluorescence-activated cell sorting (FACS). The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and mitochondrial membrane potential (mt-MP). The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1-2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells) and ALDH⁺/CD133⁺ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH⁺/CD133⁺ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells). These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH⁺/CD133⁺ subpopulation of cells.

Kyrkou A, Stellas D, Syrrou M, et al.
Generation of human induced pluripotent stem cells in defined, feeder-free conditions.
Stem Cell Res. 2016; 17(2):458-460 [PubMed] Related Publications
Herein, we describe a modified protocol for the generation of human induced pluripotent stem cells (hiPS) and expansion under defined, serum free and feeder free conditions. These cells exhibit a high level of plasticity towards various differentiation pathways both in vitro and in vivo. Ultimately, hiPS-derived lines achieved high standards of three dimensional differentiations on biomaterial scaffolds and promoted in vivo regeneration of complex organs, such as Anterior Cruciate Ligament (in swine ACL-rupture models) and other tissues as well.

Mnich E, Kowalewicz-Kulbat M, Sicińska P, et al.
Impact of Helicobacter pylori on the healing process of the gastric barrier.
World J Gastroenterol. 2016; 22(33):7536-58 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
AIM: To determine the impact of selected well defined Helicobacter pylori (H. pylori) antigens on gastric barrier cell turnover.
METHODS: In this study, using two cellular models of gastric epithelial cells and fibroblasts, we have focused on exploring the effects of well defined H. pylori soluble components such as glycine acid extract antigenic complex (GE), subunit A of urease (UreA), cytotoxin associated gene A protein (CagA) and lipopolysaccharide (LPS) on cell turnover by comparing the wound healing capacity of the cells in terms of their proliferative and metabolic activity as well as cell cycle distribution. Toxic effects of H. pylori components have been assessed in an association with damage to cell nuclei and inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation.
RESULTS: We showed that H. pylori GE, CagA and UreA promoted regeneration of epithelial cells and fibroblasts, which is necessary for effective tissue healing. However, in vivo increased proliferative activity of these cells may constitute an increased risk of gastric neoplasia. In contrast, H. pylori LPS showed a dose-dependent influence on the process of wound healing. At a low concentration (1 ng/mL) H. pylori LPS accelerated of healing epithelial cells, which was linked to significantly enhanced cell proliferation and MTT reduction as well as lack of alterations in cell cycle and downregulation of epidermal growth factor (EGF) production as well as cell nuclei destruction. By comparison, H. pylori LPS at a high concentration (25 ng/mL) inhibited the process of wound repair, which was related to diminished proliferative activity of the cells, cell cycle arrest, destruction of cell nuclei and downregulation of the EGF/STAT3 signalling pathway.
CONCLUSION: In vivo H. pylori LPS driven effects might lead to the maintenance of chronic inflammatory response and pathological disorders on the level of the gastric mucosal barrier.

Miyazaki Y, Matsubara S, Ding Q, et al.
Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition.
Mol Cancer. 2016; 15(1):49 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Pancreatic cancer is one of the most lethal malignancies. The innovative treatments are required and now the cancer stem cells (CSCs) are expected to be an effective target for novel therapies. Therefore we investigated the significance of hedgehog (Hh) signaling in the maintenance of CSC-like properties of pancreatic cancer cells, in order to discover the key molecules controlling their unique properties.
METHODS: Human pancreatic cancer cell lines, Capan-1, PANC-1, MIA PaCa-2 and Capan-1 M9 were used for our experiments in DMEM/F12 medium containing 10 % fetal bovine serum. Sphere formation assay, immunofluorescence staining, flow cytometric analysis and MTT cell viability assay were performed to investigate molecular signals and the efficacy in the treatment of pancreatic cancer cells.
RESULTS: Inhibition of the Hh pathway significantly reduced the expression of stem cell marker CD133 and sphere formation, an index of self-renewal capacity, demonstrating the suppression of CSC-like properties. Moreover, the GLI inhibitor GANT61 induced greater reduction in sphere formation and cell viability of pancreatic cancer cells than the smoothened (SMO) inhibitor cyclopamine. This suggests that GLI transcription factors, but not SMO membrane protein, are the key molecules in the Hh pathway. The treatment using GANT61 in combination with the inhibition of mTOR, which is another key molecule in pancreatic CSCs, resulted in the efficient reduction of cell viability and sphere formation of an inhibitor-resistant cell line, showing the strong efficacy and wide range applicability to pancreatic CSC-like cells.
CONCLUSIONS: Thus, this novel combination treatment could be useful for the control of pancreatic cancer by targeting pancreatic CSCs. This is the first report of the efficient elimination of pancreatic cancer stem-like cells by the double blockage of Hh/GLI and mTOR signaling.

Abozeid SM, Hathout RM, Abou-Aisha K
Silencing of the metastasis-linked gene, AEG-1, using siRNA-loaded cholamine surface-modified gelatin nanoparticles in the breast carcinoma cell line MCF-7.
Colloids Surf B Biointerfaces. 2016; 145:607-616 [PubMed] Related Publications
Cholamine surface-modified gelatin nanoparticles prepared by the double desolvation method using acetone as a dehydrating agent were selected and potentially evaluated as non viral vectors of siRNA targeting a metastatic gene AEG-1 in MCF-7 breast carcinoma cells. The ability of modified gelatin nanoparticle to complex and deliver siRNA for gene silencing was investigated. Hence, Particle size, surface charge (zeta potential) and morphology of siRNA/Gelatin nanoparticles (siGNPs) were characterized via dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscope (TEM). Moreover, the nanoparticles cytotoxicity, loading efficiency and interaction with MCF-7 human breast carcinoma cells were evaluated. Cationized GNPs of mean size range of 174nm and PDI of 0.101 were produced. The loading efficiency of siGNPs at a Nitrogen/Phosphate (N/P) ratio (w/w) of 200:1 was approximately 96%. Cellular uptake was evaluated after FITC conjugation where the particles produced high transfection efficiency. Finally, ELISA analysis of AEG-1/MTDH expression demonstrated the gene silencing effect of siGNPs, as more than 75% MTDH protein were inhibited. Our data indicate that cholamine modified GNPs pose a promising non-viral siRNA carrier for altering gene expression in MCF-7 breast cancer cells with many advantages such as relatively high gene transfection efficiency and efficient silencing ability.

Rao DD, Jay C, Wang Z, et al.
Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma.
Mol Ther. 2016; 24(8):1412-22 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing's sarcoma. Clinical-grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85-92% was demonstrated in vitro in type 1 human Ewing's sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing's sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low- and high-dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing.

Flisikowska T, Kind A, Schnieke A
Pigs as models of human cancers.
Theriogenology. 2016; 86(1):433-7 [PubMed] Related Publications
Recent decades have seen revolutionary advances in our understanding of cancer, with the molecular mechanisms underlying many human cancers now reasonably well understood. The challenge now is to bridge the gap between laboratory and clinical oncology, so these accomplishments can be translated into practical benefits for human patients. Although genetically modified mice are powerful tools to investigate the molecular basis of many human diseases, they are less suitable for many preclinical studies. Other animals can provide important complementary resources to aid the development, validation, and application of new medicines and procedures. Powerful methods of genetic engineering have now been extended to physiologically more relevant species, particularly the pig, opening the prospect of more representative, genetically defined, cancer models at human scale. Here, we provide a brief review of the genetically modified porcine cancer models described in the scientific literature.

Mazumder TH, Uddin A, Chakraborty S
Transcription factor gene GATA2: Association of leukemia and nonsynonymous to the synonymous substitution rate across five mammals.
Genomics. 2016; 107(4):155-61 [PubMed] Related Publications
GATA2 gene encodes a member of the GATA family of zinc-finger transcription factors that play a pivotal role during the transition of primitive blood forming cells into white blood cells. Mutation in GATA2 results in the loss of function or even gain of function, including abnormal proliferation of white blood cells that may predispose to acute myeloid leukemia. Our results showed that the codon usage in GATA2 has been influenced by GC mutation bias where nature has highly favored fourteen most over represented codons but disfavored the ATA codon across five mammals. Purifying natural selection has affected GATA2 gene in human and other mammals to maintain its protein function during the period of evolution. Our findings report an insight into the codon usage patterns in gaining the clues for codon optimization to alter the translational efficiency as well as for the functional conservation of gene expression and the significance of nucleotide composition in GATA2 gene within mammals.

Li G, Gao K, Chi Y, et al.
Upregulation of connexin43 contributes to PX-12-induced oxidative cell death.
Tumour Biol. 2016; 37(6):7535-46 [PubMed] Related Publications
Thioredoxin (Trx) is a small redox protein that underlies aggressive tumor growth and resistance to chemotherapy. Inhibition of Trx with the chemical inhibitor PX-12 suppresses tumor growth and induces cell apoptosis. Currently, the mechanism underlying the therapeutic actions of PX-12 and the molecules influencing cell susceptibility to PX-12 are incompletely understood. Given that connexin43 (Cx43), a tumor suppressor, regulates tumor cell susceptibility to chemotherapy, we examined the possible involvement of Cx43 in PX-12-induced cell death. Exposure of cells to PX-12 led to a loss of cell viability, which was associated with the activation of oxidative sensitive c-Jun N-terminal kinase (JNK). Inhibition of JNK or supplement of cells with anti-oxidants prevented the cell-killing action of PX-12. The forced expression of Cx43 in normal and tumor cells increased cell sensitivity to PX-12-induced JNK activation and cell death. In contrast, the downregulation of Cx43 with siRNA or the suppression of gap junctions with chemical inhibitors attenuated JNK activation and enhanced cell resistance to PX-12. Further analysis revealed that PX-12 at low concentrations induced a JNK-dependent elevation in the Cx43 protein, which was also preventable by supplementing the cells with anti-oxidants. Our results thus indicate that Cx43 is a determinant in the regulation of cell susceptibility to PX-12 and that the upregulation of Cx43 may be an additional mechanism by which PX-12 exerts its anti-tumor actions.

Yao X, Dong Z, Zhang Q, et al.
Epithelial ovarian cancer stem-like cells expressing α-gal epitopes increase the immunogenicity of tumor associated antigens.
BMC Cancer. 2015; 15:956 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: As ovarian cancer stem cells (CSCs) are responsible for tumor initiation, invasion, metastasis, and chemo-resistance, new stratagems that selectively target ovarian CSCs are critically significant. Our previous work have demonstrated that ovarian cancer spheroid cells are tumorigenic and chemo-resistant, and have the properties of ovarian CSCs. Herein, we hypothesized that expressing α-gal epitopes on ovarian spheroid cells may help eliminate CSCs and improve the outcome of therapeutic intervention for ovarian cancer patients.
METHODS: Lentivirus-mediated transfer of a pig α(1,3)galactosyltransferase [α1,3GT] enzyme gene into human ovarian cell line SKOV3 cells formed α-gal epitope-expressing cells (SKOV3-gal cells), and then these cells were maintained in a serum-free culture system to form SKOV3-gal spheroid cells. Efficacy of this cell vaccine was demonstrated in α1,3GT knockout mice (α1,3GT KO mice).
RESULTS: The antibody titers to α-gal epitopes measured by ELISA were significantly increased in α1,3GT KO mice after immunization with SKOV3-gal spheroid cells. Furthermore, compared with the non-immunized KO mice, the SKOV3 tumors grafted under renal capsules of KO mice immunized with SKOV3-gal spheroid cells grew slower and began to shrink on day 12. Western blot analysis also showed that immunized KO mice can produce effective antibody against certain tumor associated antigens (TAAs) derived from both SKOV3 cells and SKOV3 spheroid cells. The TAAs were further investigated by mass spectrometry and RNA interference (RNAi) technology. The results suggested that antibodies responding to protein c-erbB-2 may be raised in the sera of the mice after immunization with SKOV3-gal spheroid cells. Ultimately, vaccination with SKOV3-gal spheroid cells induced more CD3+CD4+T cells in the spleen of immunized mice than non-immunized KO mice.
CONCLUSIONS: The results suggest that vaccination using ovarian cancer stem-like cells engineered to express α-gal epitopes may be a novel strategy for treatment of ovarian cancer.

Janich C, Wölk C, Erdmann F, et al.
Composites of malonic acid diamides and phospholipids--Impact of lipoplex stability on transfection efficiency.
J Control Release. 2015; 220(Pt A):295-307 [PubMed] Related Publications
The use of cationic lipids as gene delivery systems is a basic method in gene therapy. Through ongoing research, lipofection is currently the leader of non-viral vectors in clinical trials. However, in order to unleash the full potential of lipofection further intensive investigations are indispensable. In this study, various lipoplex formulations were compared regarding their ability to bind DNA. To obtain information about a possible premature release of DNA at the cell surface, heparin and chondroitin dependent lipoplex destabilization experiments were carried out. Complementary investigations in cell culture were performed to quantify DNA outside the cell. Additionally, DNase I stability was investigated. In this regard a multitude of methods, namely confocal laser scanning microscopy (CLSM), polymerase chain reaction (PCR), cell culture experiments, ethidium bromide assay, gel electrophoresis, Langmuir-isotherm experiments, infrared reflection absorption spectroscopy (IRRAS), Brewster angle microscopy (BAM), zeta-(ζ)-potential measurements, and dynamic light scattering (DLS), were applied. Although the complexation of DNA is a fundamental step, we show that the DNA release by biological agents (proteoglycans) and an unsuccessful cell attachment are major transfection limiting parameters.

Misra SK, Ghoshal G, Gartia MR, et al.
Trimodal Therapy: Combining Hyperthermia with Repurposed Bexarotene and Ultrasound for Treating Liver Cancer.
ACS Nano. 2015; 9(11):10695-10718 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Repurposing of existing cancer drugs to overcome their physical limitations, such as insolubility, represents an attractive strategy to achieve enhanced therapeutic efficacy and broaden the range of clinical applications. Such an approach also promises to offer substantial cost savings in drug development efforts. Here we repurposed FDA-approved topical agent bexarotene (Targretin), currently in limited use for cutaneous manifestations of T-cell lymphomas, and re-engineer it for use in solid tumor applications by forming self-assembling nanobubbles. Physico-chemical characterization studies of the novel prodrug nanobubbles demonstrated their stability, enhanced target cell internalization capability, and highly controlled release profile in response to application of focused ultrasound energy. Using an in vitro model of hepatocellular carcinoma and an in vivo large animal model of liver ablation, we demonstrate the effectiveness of bexarotene prodrug nanobubbles when used in conjunction with catheter-based ultrasound, thereby highlighting the therapeutic promise of this trimodal approach.

Vinogradov AE
Accelerated pathway evolution in mouse-like rodents involves cell cycle control.
Mamm Genome. 2015; 26(11-12):609-18 [PubMed] Related Publications
Rodents include both the cancer-susceptible short-lived mouse and the two unrelated cancer-resistant long-lived mole-rats. In this work, their genomes were analyzed with the goal to reveal pathways enriched in genes, which are more similar between the mole-rats than between the mouse and the naked mole-rat. The pathways related to cell cycle control were prominent. They include external signal transduction and all cell cycle stages. There are several stem cell pathways among them. The other enriched pathways involve ubiquitin-dependent protein degradation, immunity, mRNA splicing, and apoptosis. The ubiquitin-dependent protein degradation is a core of network of enriched pathways. However, this phenomenon is not specific for the mouse and the mole-rats. The other muroid species show features similar to the mouse, whereas the non-muroid rodents and the human show features similar to the mole-rats. The higher ratio of non-synonymous to synonymous nucleotide substitutions (dN/dS) indicates the accelerated evolution of revealed pathways in the muroid rodents (except the blind mole-rat). Paradoxically, the dN/dS averaged over the whole genome is lower in the muroids, i.e., the purifying selection is generally stronger in them. In practical sense, these data suggest caveat for using muroid rodents (mouse, rat, and hamsters) as biomedical models of human conditions involving cell cycle and show the network of pathways where muroid genes are most different (compared with non-muroid) from human genes. The guinea pig is emphasized as a more suitable rodent model for biomedical research involving cell cycle.

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