Gene Summary

Gene:SDC4; syndecan 4
Aliases: SYND4
Summary:The protein encoded by this gene is a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. The encoded protein is found as a homodimer and is a member of the syndecan proteoglycan family. This gene is found on chromosome 20, while a pseudogene has been found on chromosome 22. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (26)
Pathways:What pathways are this gene/protein implicaed in?
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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

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

  • Protein-Tyrosine Kinases
  • Breast Cancer
  • Thrombospondin 1
  • Histocompatibility Antigens Class II
  • Bladder Cancer
  • Non-Small Cell Lung Cancer
  • Steroids
  • Cell Adhesion
  • Lung Cancer
  • Syndecan-3
  • Western Blotting
  • Cell Cycle
  • Proteoglycans
  • Protein Kinase Inhibitors
  • Syndecan-4
  • Gene Expression Profiling
  • ras Proteins
  • Adenocarcinoma
  • Brain Tumours
  • Syndecan-2
  • Proto-Oncogene Proteins
  • Chromosome 20
  • Oncogene Fusion Proteins
  • Transcription
  • Signal Transduction
  • Antigens, Differentiation, B-Lymphocyte
  • Syndecan-1
  • Cancer Gene Expression Regulation
  • Adenocarcinoma of Lung
  • Extracellular Matrix Proteins
  • Biglycan
  • Cell Cycle Proteins
  • Proteomics
  • Membrane Glycoproteins
  • Radiation Tolerance
  • Brain Tumours
  • Messenger RNA
  • Staging
  • Urothelium
  • Heparan Sulfate Proteoglycans
  • Amino Acid Substitution
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: SDC4 (cancer-related)

Reyes I, Reyes N, Suriano R, et al.
Gene expression profiling identifies potential molecular markers of papillary thyroid carcinoma.
Cancer Biomark. 2019; 24(1):71-83 [PubMed] Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases.
OBJECTIVE: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease.
METHODS: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response.
RESULTS: In this study we found that upregulation of extracellular activities, such as proteoglycans, ECM-receptor interaction, and cell adhesion molecules, were the most prominent feature of PTC. Significantly over-expressed genes included SDC1 (syndecan 1), SDC4 (syndecan 4), KLK7 (kallikrein-related peptidase 7), KLK10 (kallikrein-related peptidase 10), SLPI (secretory leukocyte peptidase inhibitor), GDF15 (growth/differentiation factor-15), ALOX5 (arachidonate 5-lipoxygenase), SFRP2 (secreted Frizzled-related protein 2), among others. Further, elevated KLK10 levels were detected in patients with PTC. Many of these genes belong to KEGG pathway "Proteoglycans in cancer".
CONCLUSIONS: Using DNA microarray analysis allowed the identification of genes and pathways with known important roles in malignant transformation, and also the discovery of novel genes that may be potential biomarkers for PTC.

Chen LL, Gao GX, Shen FX, et al.
SDC4 Gene Silencing Favors Human Papillary Thyroid Carcinoma Cell Apoptosis and Inhibits Epithelial Mesenchymal Transition
Mol Cells. 2018; 41(9):853-867 [PubMed] Free Access to Full Article Related Publications
As the most common type of endocrine malignancy, papillary thyroid cancer (PTC) accounts for 85-90% of all thyroid cancers. In this study, we presented the hypothesis that SDC4 gene silencing could effectively attenuate epithelial mesenchymal transition (EMT), and promote cell apoptosis

López-Aguilar JE, Velázquez-Flores MA, Simón-Martínez LA, et al.
Circulating microRNAs as Biomarkers for Pediatric Astrocytomas.
Arch Med Res. 2017; 48(4):323-332 [PubMed] Related Publications
BACKGROUND AND AIMS: Since MicroRNAs (miRNAs) are potent regulators of gene expression, their expression and function alterations are associated with different types of cancer, including pediatric astrocytoma. Since the secretion of miRNAs by tumors into corporal fluids has made it possible to identify biomarkers in cancer, their deter mination in pediatric astrocytoma is vital. In order to gain insight into the mechanisms controlled by miRNAs in these neoplasms, we tested the expression of miRNAs 130a, 145, 335, 1303, and let-7g-3p by qPCR in tumors and blood serum from pediatric patients with astrocytoma. The data was analyzed with the DIANA-miRPath v3.0 platform.
RESULTS: The data represented expression changes of all mirRNAs tested in both tumors and blood serum, which strongly suggest their use as circulating biomarkers for astrocytic tumors. The bioinformatic analysis -with DIANA-miRPath v3.0- showed the involvement of these miRNAs in extracellular matrix (ECM)-receptor interaction and proteoglycans in cancer, which control many hallmarks of cancer. In fact, the expression of the proteoglycan syndecan 4 (SDC4) and that of its biosynthetic enzymes, Exostosin Glycosyltransferase 1 (EXT1) and Xylosyltransferase 1 (XYLT1), were altered in pediatric astrocytoma.
CONCLUSIONS: Our results highlight the role of microRNAs in the biology of pediatric astrocytoma and demonstrated for the first time the potential use of some circulating microRNAs as non-invasive biomarkers for this type of tumors, particularly miRs 130a, 145, and 335.

Wang L, Collings CK, Zhao Z, et al.
A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism.
Genes Dev. 2017; 31(20):2056-2066 [PubMed] Free Access to Full Article Related Publications
Mutations and translocations within the COMPASS (complex of proteins associated with Set1) family of histone lysine methyltransferases are associated with a large number of human diseases, including cancer. Here we report that SET1B/COMPASS, which is essential for cell survival, surprisingly has a cytoplasmic variant. SET1B, but not its SET domain, is critical for maintaining cell viability, indicating a novel catalytic-independent role of SET1B/COMPASS. Loss of SET1B or its unique cytoplasmic-interacting protein, BOD1, leads to up-regulation of expression of numerous genes modulating fatty acid metabolism, including

Zhu YC, Lin XP, Li XF, et al.
Concurrent ROS1 gene rearrangement and KRAS mutation in lung adenocarcinoma: A case report and literature review.
Thorac Cancer. 2018; 9(1):159-163 [PubMed] Free Access to Full Article Related Publications
Lung adenocarcinomas with gene rearrangement in the receptor tyrosine kinase ROS1 have emerged as a rare molecular subtype. Although these lung adenocarcinomas respond to ROS1tyrosine kinase inhibitors, many patients ultimately acquire resistance. ROS1gene rearrangement is generally mutually exclusive with other driver genomic alterations, such as those in EGFR, KRAS, or ALK, thus multiple genomic alterations are extremely rare. Herein, we report a case of a 42-year-old man diagnosed with lung adenocarcinoma positive for a SDC4-ROS1 fusion, who was treated with crizotinib followed by three cycles of chemotherapy. A biopsy acquired after disease progression revealed the original SDC4-ROS1 fusion along with a KRAS point mutation (p.G12D).We reviewed the related literature to determine the frequency of gene mutations in non-small cell lung cancer patients. A better understanding of the molecular biology of non-small cell lung cancer with multiple driver genomic aberrations will assist in determining optimal treatment.

Jones MR, Lim H, Shen Y, et al.
Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.
Ann Oncol. 2017; 28(12):3092-3097 [PubMed] Related Publications
Background: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown.
Patients and methods: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization.
Results: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib.
Conclusion: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin.
Clinical trial information: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).

Roskoski R
ROS1 protein-tyrosine kinase inhibitors in the treatment of ROS1 fusion protein-driven non-small cell lung cancers.
Pharmacol Res. 2017; 121:202-212 [PubMed] Related Publications
ROS1 protein-tyrosine kinase fusion proteins are expressed in 1-2% of non-small cell lung cancers. The ROS1 fusion partners include CD74, CCDC6, EZR, FIG, KDELR2, LRIG3, MSN, SDC4, SLC34A2, TMEM106B, TMP3, and TPD52L1. Physiological ROS1 is closely related to the ALK, LTK, and insulin receptor protein-tyrosine kinases. ROS1 is a so-called orphan receptor because the identity of its activating ligand, if any, is unknown. The receptor is expressed during development, but little is expressed in adults and its physiological function is unknown. The human ROS1 gene encodes 2347 amino acid residues and ROS1 is the largest protein-tyrosine kinase receptor protein. Unlike the ALK fusion proteins that are activated by the dimerization induced by their amino-terminal portions, the amino-terminal domains of several of its fusion proteins including CD74 apparently lack the ability to induce dimerization so that the mechanism of constitutive protein kinase activation is unknown. Downstream signaling from the ROS1 fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module, the phosphatidyl inositol 3-kinase cell survival pathway, and the Vav3 cell migration pathway. Moreover, several of the ROS1 fusion proteins are implicated in the pathogenesis of a very small proportion of other cancers including glioblastoma, angiosarcoma, and cholangiocarcinoma as well as ovarian, gastric, and colorectal carcinomas. The occurrence of oncogenic ROS1 fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ROS1 inhibitors. Although the percentage of lung cancers driven by ROS1 fusion proteins is low, owing to the large number of new cases of non-small cell lung cancer per year, the number of new cases of ROS1-positive lung cancers is significant and ranges from 2000 to 4000 per year in the United States and 10,000-15,000 worldwide. Crizotinib was the first inhibitor approved by the US Food and Drug Administration for the treatment of ROS1-positive non-small cell lung cancer in 2016. Other drugs that are in clinical trials for the treatment of these lung cancers include ceritinib, cabozantinib, entrectinib, and lorlatinib. Crizotinib forms a complex within the front cleft between the small and large lobes of an active ROS1 protein-kinase domain and it is classified as type I inhibitor.

Inoue M, Toki H, Matsui J, et al.
Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.
Carcinogenesis. 2016; 37(5):452-60 [PubMed] Related Publications
ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most frequently detected fusions, CD74-ROS1, as well as another SDC4-ROS1 fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the two ROS1-fusion genes specifically in lung alveolar type II cells. Mice in all TG lines developed tumorigenic nodules in the lung, and a few strains of both TG mouse lines demonstrated early-onset nodule development (multiple tumor lesions present in the lung at 2-4 weeks after birth); therefore, these two strains were selected for further investigation. Tumors developed progressively in the untreated TG mice of both lines, whereas those receiving oral administration of an ALK/MET/ROS1 inhibitor, crizotinib, and an ALK/ROS1 inhibitor, ASP3026, showed marked reduction in the tumor burden. Collectively, these data suggest that each of these two ROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinoma in vivo The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents against ROS1-fusion-positive lung cancer.

Fu S, Liang Y, Lin YB, et al.
The Frequency and Clinical Implication of ROS1 and RET Rearrangements in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Patients.
PLoS One. 2015; 10(4):e0124354 [PubMed] Free Access to Full Article Related Publications
To evaluate the frequency and clinicopathological features of ROS1 and RET rearrangements in N2 node positive stage IIIA (IIIA-N2) non-small cell lung cancer (NSCLC) patients, we retrospectively screened 204 cases with a tissue microarray (TMA) panel by fluorescent in situ hybridization (FISH), and confirmed by direct sequencing and immunohistochemistry (IHC). The relationship between ROS1 or RET rearrangements, clinicopathological features, and prognostic factors were analyzed in resected stage IIIA-N2 NSCLC. Of the 204 cases, 4 cases were confirmed with ROS1 rearrangement, but no RET rearrangement was detected. All 4 ROS1-rearranged cases were adenocarcinomas. The predominant pathological type was acinar pattern in ROS1-rearranged tumors, except for 1 case harboring a mixture acinar and mucous tumor cells. Variants of ROS1 rearrangement were SDC4-ROS1 (E2:E32), SDC4-ROS1 (E4:E32) and SDC4-ROS1 (E4:E34). There was no significant association between ROS1 rearrangement and clinicopathological characteristics. In this cohort, multivariate analysis for overall survival (OS) indicated that squamous cell carcinoma and lobectomy were independent predictors of poor prognosis; R0 surgical resection and non-pleural invasion were independent predictors of good prognosis. In resected stage IIIA-N2 NSCLC patients, ROS1-rearranged cases tended to occur in younger patients with adenocarcinomas. The prognosis of resected stage IIIA-N2 is generally considered poor, but patients with ROS1 rearrangement will benefit from the targeted therapy.

Okolicsanyi RK, Buffiere A, Jacinto JM, et al.
Association of heparan sulfate proteoglycans SDC1 and SDC4 polymorphisms with breast cancer in an Australian Caucasian population.
Tumour Biol. 2015; 36(3):1731-8 [PubMed] Related Publications
Breast cancer is a common disease in both developing and developed countries with early identification and treatment improving prognosis and survival. Heparan sulfate proteoglycans (HSPGs) are key components of the extracellular matrix (ECM) that mediate cell adhesion, motility, proliferation, invasion and cell signalling. Members of the syndecan family of HSPGs have been identified to be involved in breast cancer progression through their varied interactions with a number of growth factors, ligands and receptors. Specifically, high expression levels of syndecan-1 (SDC1) have been demonstrated in more invasive breast tumours while elevated syndecan-4 (SDC4) levels have been identified to correspond with improved prognosis. With genetic changes in the syndecans and their association with breast cancers plausible, we examined two single nucleotide polymorphisms in SDC1 (rs1131351) and SDC4 (rs67068737) within an Australian Caucasian breast cancer case/control population. No association was found with SDC4 and breast cancer in our population. However, a significant association between SDC1 and breast cancer was identified in both our case/control population and in a replication cohort. When both populations were combined for analysis, this association became more significant (genotype, p = 0.0003; allele, p = 0.0001). This data suggests an increased risk of developing breast cancer associated with the presence of the C allele of the SDC1 rs1131351 single nucleotide polymorphism (SNP) and may provide a marker toward early breast cancer detection.

Chen YF, Hsieh MS, Wu SG, et al.
Clinical and the prognostic characteristics of lung adenocarcinoma patients with ROS1 fusion in comparison with other driver mutations in East Asian populations.
J Thorac Oncol. 2014; 9(8):1171-9 [PubMed] Related Publications
INTRODUCTION: The prevalence, demographic features, and clinical outcomes of lung adenocarcinoma patients with novel ROS1 oncogenic rearrangement in East Asian populations are not clear. This study aimed to investigate the clinical and prognostic characteristics of lung adenocarcinoma in patients with ROS1 fusion compared with other driver mutations.
METHODS: Multiplex reverse transcription-polymerase chain reaction was used to detect the ROS1 fusion gene in lung adenocarcinoma cases. Immunohistochemistry was used to confirm the expression of ROS1. The demographic data and clinical outcomes of patients with the ROS1 fusion gene were compared with those of patients without the ROS1 fusion gene, including those with the EGFR mutation, EML4-ALK fusion, KRAS mutation, and quadruple-negative patients.
RESULTS: Of 492 patients with lung adenocarcinoma, 12 (2.4%) had the ROS1 fusion gene. Their median age was 45.0 years, significantly younger than that of the ROS1 fusion-negative cohorts (p < 0.001). Acinar (including cribriform) and solid patterns were the two most common histologic subtypes in the ROS1 fusion tumors (7 of 12, 58.3%) and were predominantly seen in CD74-ROS1 fusion tumors (66.7%). There was no significant survival difference between the ROS1 fusion-positive and ROS1 fusion-negative cohorts in surgical group, but ROS1 fusion-positive patients might have worse outcomes than EGFR-mutant patients in the stage IV group.
CONCLUSIONS: The ROS1 fusion gene can be successfully detected in East Asian patients with lung adenocarcinoma using multiplex reverse transcription-polymerase chain reaction. These patients tend to be younger and have characteristic histologic subtypes. Due to the small number of ROS1 fusion patients, the prognostic value of ROS1 fusion need further studies to confirm.

Katoh M
Functional proteomics, human genetics and cancer biology of GIPC family members.
Exp Mol Med. 2013; 45:e26 [PubMed] Free Access to Full Article Related Publications
GIPC1, GIPC2 and GIPC3 consist of GIPC homology 1 (GH1) domain, PDZ domain and GH2 domain. The regions around the GH1 and GH2 domains of GIPC1 are involved in dimerization and interaction with myosin VI (MYO6), respectively. The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins [IGF1R, NTRK1, ADRB1, DRD2, TGFβR3 (transforming growth factorβ receptor type III), SDC4, SEMA4C, LRP1, NRP1, GLUT1, integrin α5 and VANGL2], cytosolic signaling regulators (APPL1 and RGS19) and viral proteins (HBc and HPV-18 E6). GIPC1 is an adaptor protein with dimerizing ability that loads PDZ ligands as cargoes for MYO6-dependent endosomal trafficking. GIPC1 is required for cell-surface expression of IGF1R and TGFβR3. GIPC1 is also required for integrin recycling during cell migration, angiogenesis and cytokinesis. On early endosomes, GIPC1 assembles receptor tyrosine kinases (RTKs) and APPL1 for activation of PI3K-AKT signaling, and G protein-coupled receptors (GPCRs) and RGS19 for attenuation of inhibitory Gα signaling. GIPC1 upregulation in breast, ovarian and pancreatic cancers promotes tumor proliferation and invasion, whereas GIPC1 downregulation in cervical cancer with human papillomavirus type 18 infection leads to resistance to cytostatic transforming growth factorβ signaling. GIPC2 is downregulated in acute lymphocytic leukemia owing to epigenetic silencing, while Gipc2 is upregulated in estrogen-induced mammary tumors. Somatic mutations of GIPC2 occur in malignant melanoma, and colorectal and ovarian cancers. Germ-line mutations of the GIPC3 or MYO6 gene cause nonsyndromic hearing loss. As GIPC proteins are involved in trafficking, signaling and recycling of RTKs, GPCRs, integrins and other transmembrane proteins, dysregulation of GIPCs results in human pathologies, such as cancer and hereditary deafness.

Erdem M, Erdem S, Sanli O, et al.
Up-regulation of TGM2 with ITGB1 and SDC4 is important in the development and metastasis of renal cell carcinoma.
Urol Oncol. 2014; 32(1):25.e13-20 [PubMed] Related Publications
OBJECTIVE: Tissue transglutaminase (TGM2) up-regulation is involved in the progression and dissemination of carcinomas through β1 integrin (ITGB1) association. Given that TGM2 interaction with syndecan-4 (SDC4) on the cell surface is important in the activation of ITGB1 and integrin-mediated survival signaling, we investigated the roles of TGM2, ITGB1, and SDC4 in the development and metastasis of renal cell carcinoma (RCC).
MATERIAL AND METHODS: Expression levels of TGM2, ITGB1, and SDC4 mRNA were analyzed in primary tumor samples (n = 95) and their healthy counterparts in addition to control and RCC epithelial cell lines. TGM2 catalytic activity in 60 randomly selected patient samples was measured by enzyme-linked sorbent plate assay.
RESULTS: TGM2 expression ratio showed a significant 2.9-fold decrease in 67 (70.5%) of the primary RCC tumors (P <0.0001) independent of clinical covariates, including tumor node metastasis (TNM) staging and histopathologic grading. For the remaining 28 (29.5%) tumors, a 1.95-fold increase was recorded in the TGM2 expression levels, which also showed a significant increase in ITGB1 and SDC4 expression levels in 82.6% of the overexpression cases (P <0.001). Up-regulation of TGM2 along with ITGB1 and SCD4 was associated with metastasis and a marked decrease in tumor necrosis. Consistently, RCC cell lines exhibited higher levels of TGM2 expression compared with the control epithelial cell line with a significant up-regulation of ITGB1 and SCD4 recorded for the metastatic lines.
CONCLUSIONS: Our findings suggest that TGM2 up-regulation along with ITGB1 and SDC4 plays an important role in the development of RCC tumors and advanced RCC with metastasis.

Malavaki CJ, Roussidis AE, Gialeli C, et al.
Imatinib as a key inhibitor of the platelet-derived growth factor receptor mediated expression of cell surface heparan sulfate proteoglycans and functional properties of breast cancer cells.
FEBS J. 2013; 280(10):2477-89 [PubMed] Related Publications
Cell surface heparan sulfate proteoglycans (HSPGs), syndecans and glypicans, play crucial roles in the functional properties of cancer cells, such as proliferation, adhesion, migration and invasion. Platelet-derived growth factor (PDGF)/PDGF receptor (PDGF-R) mediated signaling, on the other hand, is highly associated with cancer progression. Specifically, PDGF-Rα and PDGF-Rβ expressions documented in breast cancer tissue specimens as well as breast cancer cell lines are correlated with tumor aggressiveness and metastasis. Imatinib (Glivec(®)) is a tyrosine kinase inhibitor specific for PDGF-Rs, c-ΚΙΤ and BCR-ABL. In this study we evaluated the effects of imatinib on the properties of breast cancer cells as well as on the expression of HSPGs in the presence and absence of PDGF-BB. These studies have been conducted in a panel of three breast cancer cell lines of low and high metastatic potential. Our results indicate that imatinib exerts a significant inhibitory effect on breast cancer cell proliferation, invasion and migration as well as on the cell surface expression of HSPGs even after exposure of PDGF. These effects depend on the aggressiveness of breast cancer cells and the type of HSPG. It is suggested that imatinib may be of potential therapeutic usefulness in breast cancer regimes.

Tsonis AI, Afratis N, Gialeli C, et al.
Evaluation of the coordinated actions of estrogen receptors with epidermal growth factor receptor and insulin-like growth factor receptor in the expression of cell surface heparan sulfate proteoglycans and cell motility in breast cancer cells.
FEBS J. 2013; 280(10):2248-59 [PubMed] Related Publications
Estradiol (E2)-estrogen receptor (ER) actions are implicated in initiation, growth and progression of hormone-dependent breast cancer. Crosstalk between ERs, epidermal growth factor receptor (EGFR) and/or insulin-like growth factor receptor (IGFR) is critical for the observed resistance to endocrine therapies. Cell surface heparan sulfate proteoglycans (HSPGs) are principal mediators of cancer cell properties and the E2-ER pathway as well as those activated by EGFR and IGFR have significant roles in regulating the expression of certain cell surface HSPGs, such as syndecan-2 (SDC-2), syndecan-4 (SDC-4) and glypican-1. In this study, we therefore evaluated the role of EGFR-IGFR signaling on the constitutive expression and E2-mediated expression of ERs and HSPGs as well as the effect of E2-ERs and IGFR/EGFR-mediated cell migration in ERα+ (MCF-7) and ERβ+ (MDA-MB-231) breast cancer cells using specific intracellular inhibitors of EGFR and IGFR. We report that the expression of ERα is mainly enhanced by IGFR, whereas ERβ expression is mainly coordinated by EGFR. Moreover, constitutive SDC-2 expression in ERα+ and ERβ+ cells is mainly mediated through the IGFR, whereas in ERα+ E2-treated cells EGFR is the active one. In contrast, SDC-4 expression is regulated by IGFR in the presence and absence of E2. E2 also seems to diminish the inhibitory effect of EGFR and IGFR inhibitors in breast cancer cell migration. These data suggest that the coordinated action of ERs with EGFR and/or IGFR is of crucial importance, providing potential targets for designing and developing novel multi-potent agents for endocrine therapies.

Gialeli Ch, Theocharis AD, Kletsas D, et al.
Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab.
Invest New Drugs. 2013; 31(3):516-24 [PubMed] Related Publications
The epidermal growth factor receptor (EGFR) is a member of the HER family receptors and its activation induced by its natural ligand EGF results in colon cancer growth and progression. Panitumumab (pmAb) is a fully human IgG2 anti-EGFR antibody that blocks the EGFR actions. In the present study, we evaluated the effects of pmAb on the EGF-mediated cellular responses in a panel of colon cancer cells (HCT-8, HT-29, DLD-1 and HCT-116). HCT-1116 and DLD-1 cells showed no significant EGF-dependent cell proliferation; HT-29 and HCT-8 exhibited an EGF-dependent proliferation, with HCT-8 cells to be the most responsive with significant EGFR phosphorylation upon treatment with EGF. The effects of pmAb were then evaluated in the most EGF-responsive cells, HCT-8. In that respect, pmAb impedes the signaling cascade mediated by EGFR intracellular phosphorylation and activity of focal adhesion kinase (FAK) as well as the EGF-induced invasive and migratory potential of colon cancer cells. At the level of matrix effectors implicated in colon cancer progression we report that pmAb is a potent inhibitor of constitute and EGF-mediated gene expression of certain matrix effectors, such as membrane-type 1 metalloproteinase (MT1-MMP), extracellular metalloproteinases inducer (EMMPRIN), urokinase plasminogen activator (uPA) and syndecan-4. The obtained data demonstrated that pmAb is a specific blocker of EGF-mediated EGFR activation, resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth, migration and invasiveness as well as of matrix effector implicated in cancer progression.

Davies KD, Le AT, Theodoro MF, et al.
Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.
Clin Cancer Res. 2012; 18(17):4570-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Oncogenic gene fusions involving the 3' region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets.
EXPERIMENTAL DESIGN: An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting.
RESULTS: In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1 fusion, whereas two TMA samples expressed the CD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival.
CONCLUSIONS: ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes.

Ridgway LD, Wetzel MD, Ngo JA, et al.
Heparanase-induced GEF-H1 signaling regulates the cytoskeletal dynamics of brain metastatic breast cancer cells.
Mol Cancer Res. 2012; 10(6):689-702 [PubMed] Free Access to Full Article Related Publications
Heparanase is the only mammalian endoglycosidase which has been widely implicated in cancer because of its capability to degrade heparan sulfate chains of heparan sulfate proteoglycans (HSPG). Specifically, the cell surface HSPG syndecan-1 and -4 (SDC1 and SDC4) are modulators of growth factor action, and SDC4 is implicated in cell adhesion as a key member of focal adhesion complexes. We hypothesized that extracellular heparanase modulates brain metastatic breast cancer (BMBC) cell invasiveness by affecting cytoskeletal dynamics, SDC4 carboxy-terminal-associated proteins, and downstream targets. We used two independently derived human BMBC cell systems (MB-231BR and MB-231BR3), which possess distinct cellular morphologies and properties. Highly aggressive spindle-shaped 231BR3 cells changed to a round cell morphology associated with expression of the small GTPase guanine nucleotide exchange factor-H1 (GEF-H1). We showed that GEF-H1 is a new component of the SDC4 signaling complex in BMBC cells. Treatment with heparanase resulted in regulation of the SDC4/protein kinase C α axis while maintaining a constitutive GEF-H1 level. Third, GEF-H1 knockdown followed by cell exposure to heparanase caused a significant regulation of activities of Rac1 and RhoA, which are GEF-H1 targets and fundamental effectors in cell plasticity control. Fourth, L-heparanase augmented expression of β1 integrin in BMBC cells and of vascular cell adhesion molecule 1 (VCAM1; the major β1 integrin receptor) in human brain microvascular endothelial cells. Finally, using a newly developed blood-brain barrier in vitro model, we show that BMBC cell transmigration was significantly reduced in GEF-H1 knockdown cells. These findings implicate heparanase in mechanisms of cytoskeletal dynamics and in the cross-talk between tumor cells and vascular brain endothelium. They are of relevance because they elucidate molecular events in the initial steps leading to BMBC onset and capturing distinct roles of latent and active heparanase in the brain microenvironment.

Chang SC, Mulloy B, Magee AI, Couchman JR
Two distinct sites in sonic Hedgehog combine for heparan sulfate interactions and cell signaling functions.
J Biol Chem. 2011; 286(52):44391-402 [PubMed] Free Access to Full Article Related Publications
Hedgehog (Hh) proteins are morphogens that mediate many developmental processes. Hh signaling is significant for many aspects of embryonic development, whereas dysregulation of this pathway is associated with several types of cancer. Hh proteins require heparan sulfate proteoglycans (HSPGs) for their normal distribution and signaling activity. Here, we have used molecular modeling to examine the heparin-binding domain of sonic hedgehog (Shh). In biochemical and cell biological assays, the importance of specific residues of the putative heparin-binding domain for signaling was assessed. It was determined that key residues in human (h) Shh involved in heparin and HSPG syndecan-4 binding and biological activity included the well known cationic Cardin-Weintraub motif (lysines 32-38) but also a previously unidentified major role for lysine 178. The activity of Shh mutated in these residues was tested by quantitation of alkaline phosphatase activity in C3H10T1/2 cells differentiating into osteoblasts and hShh-inducible gene expression in PANC1 human pancreatic ductal adenocarcinoma cells. Mutated hShhs such as K37S/K38S, K178S, and particularly K37S/K38S/K178S that could not interact with heparin efficiently had reduced signaling activity compared with wild type hShh or a control mutation (K74S). In addition, the mutant hShh proteins supported reduced proliferation and invasion of PANC1 cells compared with control hShh proteins, following endogenous hShh depletion by RNAi knockdown. The data correlated with reduced Shh multimerization where the Lys-37/38 and/or Lys-178 mutations were examined. These studies provide a new insight into the functional roles of hShh interactions with HSPGs, which may allow targeting this aspect of hShh biology in, for example, pancreatic ductal adenocarcinoma.

Vuoriluoto K, Högnäs G, Meller P, et al.
Syndecan-1 and -4 differentially regulate oncogenic K-ras dependent cell invasion into collagen through α2β1 integrin and MT1-MMP.
Matrix Biol. 2011; 30(3):207-17 [PubMed] Related Publications
Syndecans function as co-receptors for integrins on different matrixes. Recently, syndecan-1 has been shown to be important for α2β1 integrin-mediated adhesion to collagen in tumor cells by regulating cell adhesion and migration on two-dimensional collagen. However, the function of syndecans in supporting α2β1 integrin interactions with three-dimensional (3D) collagen is less well studied. Using loss-of-function and overexpression experiments we show that in 3D collagen syndecan-4 supports α2β1-mediated collagen matrix contraction. Cell invasion through type I collagen containing 3D extracellular matrix (ECM) is driven by α2β1 integrin and membrane type-1 matrix metalloproteinase (MT1-MMP). Here we show that mutational activation of K-ras correlates with increased expression of α2β1 integrin, MT1-MMP, syndecan-1, and syndecan-4. While K-ras-induced α2β1 integrin and MT1-MMP are positive regulators of invasion, silencing and overexpression of syndecans demonstrate that these proteins inhibit cell invasion into collagen. Taken together, these data demonstrate the existence of a complex interplay between integrin α2β1, MT1-MMP, and syndecans in the invasion of K-ras mutant cells in 3D collagen that may represent a mechanism by which tumor cells become more invasive and metastatic.

Jerhammar F, Ceder R, Garvin S, et al.
Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma.
Cancer Biol Ther. 2010; 10(12):1244-51 [PubMed] Related Publications
Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity, and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p=0.047). In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance.

Ridgway LD, Wetzel MD, Marchetti D
Modulation of GEF-H1 induced signaling by heparanase in brain metastatic melanoma cells.
J Cell Biochem. 2010; 111(5):1299-309 [PubMed] Free Access to Full Article Related Publications
Mechanisms of brain metastatic melanoma (BMM) remain largely unknown. Understanding the modulation of signaling pathways that alter BMM cell invasion and metastasis is critical to develop new therapies for BMM. Heparanase has been widely implicated in cancer and is the dominant mammalian endoglycosidase which degrades heparan sulfate chains of proteoglycans (HSPG) including syndecans (SDCs). Recent findings also indicate that heparanase possesses non-enzymatic functions in its latent form. We hypothesized that extracellular heparanase modulates BMM cell signaling by involving SDC1/4 carboxy terminal-associated proteins and downstream targets. We digested BMM cell surface HS with human recombinant active or latent heparanase to delineate their effects on cytoskeletal dynamics and cell invasiveness. We identified the small GTPase guanine nucleotide exchange factor-H1 (GEF-H1) as a new component of a SDC signaling complex that is differentially expressed in BMM cells compared to corresponding non-metastatic counterparts. Second, knockdown of GEF-H1, SDC1, or SDC4 decreased BMM cell invasiveness and GEF-H1 modulated small GTPase activity of Rac1 and RhoA in conjunction with heparanase treatment. Third, both active and latent forms of heparanase affected Rac1 and RhoA activity; notably increasing RhoA activity. Both forms of heparanase were found to mediate the expression and subcellular localization of GEF-H1, and treatment of BMM with latent heparanase modulated SDC1/4 gene expression. Finally, treatment with exogenous heparanase downregulated BMM cell invasion. These studies indicate the relevance of heparanase signaling pathways in BMM progression, and provide insights into the molecular mechanisms regulating HSPG signaling in response to exogenous heparanase.

Marzioni D, Lorenzi T, Mazzucchelli R, et al.
Expression of basic fibroblast growth factor, its receptors and syndecans in bladder cancer.
Int J Immunopathol Pharmacol. 2009 Jul-Sep; 22(3):627-38 [PubMed] Related Publications
Basic fibroblast growth factor (bFGF) is a heparin-binding cationic protein involved in a variety of pathological conditions including angiogenesis and solid tumour growth. The basic fibroblast growth factor receptor (FGFR) family comprises at least 4 high affinity tyrosine kinase receptors that require syndecans for their function. Mounting evidence indicates that syndecans, that bind both bFGF and their FGFRs, will act as stimulators, whereas syndecans that only bind bFGF will act as inhibitors of signaling by sequestering the growth factor. Recent findings have highlighted the importance of syndecans in urological cancers. The aim of this study is to investigate the expression of bFGF, its receptors (R1 and R2) and syndecans (1-4) in invasive urothelial carcinoma and normal-looking urothelium by Western blotting, RT-PCR, and immunohistochemistry analyses. Interestingly, bFGF, FGFR1 and FGFR2 protein levels statistically increased in bladder cancer tissues. mRNA of FGFR1 and syndecans (1-4), showed a statistically significant increase while an mRNA increase in the other molecules analysed was not significant. bFGF, its receptors and syndecan immunostaining were mainly present in the urothelium both in normal-looking tissues and urothelial neoplastic cells. In conclusion, our data report that the bFGF, FGFR and syndecan expressions are altered in bladder tumours.

Nord H, Segersten U, Sandgren J, et al.
Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma.
Int J Cancer. 2010; 126(6):1390-402 [PubMed] Related Publications
Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating tumors (stage T2+). The risk of progression and death for the most frequent diagnosed type, Ta, is low, but the high incidence of recurrences has a significant effect on the patients' quality of life and poses substantial costs for health care systems. Consequently, the purpose of this study was to search for predictive factors of recurrence on the basis of genetic profiling. A clinically well characterized cohort of Ta bladder carcinomas, selected by the presence or absence of recurrences, was evaluated by an integrated analysis of DNA copy number changes and gene expression (clone-based 32K, respectively, U133Plus2.0 arrays). Only a few chromosomal aberrations have previously been defined in superficial bladder cancer. Surprisingly, the profiling of Ta tumors with a high-resolution array showed that DNA copy alterations are relatively common in this tumor type. Furthermore, we observed an overrepresentation of focal amplifications within high-grade and recurrent cases. Known (FGFR3, CCND1, MYC, MDM2) and novel candidate genes were identified within the loci. For example, MYBL2, a nuclear transcription factor involved in cell-cycle progression; YWHAB, an antiapoptotic protein; and SDC4, an important component of focal adhesions represent interesting candidates detected within two amplicons on chromosome 20, for which DNA amplification correlated with transcript up-regulation. The observed overrepresentation of amplicons within high-grade and recurrent cases may be clinically useful for the identification of patients who will benefit from a more aggressive therapy.

Watanabe A, Mabuchi T, Satoh E, et al.
Expression of syndecans, a heparan sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression.
J Neurooncol. 2006; 77(1):25-32 [PubMed] Related Publications
Invasion of tumor cells into the surrounding normal brain tissues is a prominent feature of malignant gliomas. Malignant glioma cells secrete thrombospondin-1 which participates in the motility of glioma cells and binds cell surface heparan sulfate proteoglycan. To clarify the invasion mechanism of tumor cells, expression of the syndecans (syndecan-1, -2, -3, and -4), a major cell surface heparan sulfate proteoglycan family, was analyzed in malignant gliomas. Involvement of nuclear factor-kappaB (NF-kappaB) on syndecan-1 expression was also investigated. Using reverse transcription-PCR, the authors analyzed the expression of syndecan-1, -2, -3, and -4 in 10 malignant glioma cell lines, 2 glioblastoma specimens, and 2 normal brain specimens. All malignant glioma cell lines and glioblastoma specimens expressed all types of syndecan mRNA, except in one glioma cell line that lacked syndecan-3 expression. On the other hand, normal brain specimens expressed syndecan-2, -3, and -4 mRNA, but did not syndecan-1 mRNA. Syndecan-1 protein was localized in the cell surface of all malignant glioma cell lines by flow cytometry. Various levels of active nuclear factor-kappa B (NF-kappaB) was detected in all malignant glioma cell lines using immunoblotting. The expression of active NF-kappaB and syndecan-1 increased in U251 glioma cells after tumor necrosis factor-alpha or interleukin-1beta treatment, which can activate NF-kappaB. The amplification of active NF-kappaB and syndecan-1 by tumor necrosis factor-alpha or interleukin-1beta was suppressed by an inhibitor of NF-kappaB activation (emodin). Emodin also downregulated the expression of syndecan-1 mRNA in U251 cells. These results indicate that malignant glioma cells express all types of syndecans and suggest that NF-kappaB participates in the upregulation of the syndecan-1 expression at the transcriptional level, and increased expression of syndecan-1 could associate with extracellular matrices including thrombospondin-1.

Israeli O, Goldring-Aviram A, Rienstein S, et al.
In silico chromosomal clustering of genes displaying altered expression patterns in ovarian cancer.
Cancer Genet Cytogenet. 2005; 160(1):35-42 [PubMed] Related Publications
Ovarian cancer, the leading cause of death due to gynecological malignancy, is diagnosed in most cases at an advanced stage. Combined with the paucity of symptoms of early-stage disease, the need to develop novel effective markers for the detection of potentially curable, early-stage disease is self-evident. Comprehensive analyses of somatic gene expression patterns in ovarian cancer were reported previously (n=17) and yielded substantial information on somatically altered genes, information that can potentially be useful in developing early detection markers. To further substantiate the role that these genes play in ovarian cancer tumorogenesis, we surveyed these reports and arranged the significantly altered genes from all reported studies by their chromosomal location (in silico chromosomal clustering). Subsequent comparison of this clustering to known genomic somatic alterations at the DNA level from data obtained using comparative genomic hybridization (CGH) was carried out. The major chromosomal regions that displayed overexpressed genes were correlated with the major CGH-detectable DNA amplification areas at 20q (harboring HE4, SLPI, MYBL2, UBE2C, and SDC4) and 1q (harboring MUC1). These genes may provide insights into ovarian cancer pathogenesis and may also prove to be useful as early detection tools.

Koike T, Kimura N, Miyazaki K, et al.
Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates.
Proc Natl Acad Sci U S A. 2004; 101(21):8132-7 [PubMed] Free Access to Full Article Related Publications
Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and alpha5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis.

Roberts RA, Michel C, Coyle B, et al.
Regulation of apoptosis by peroxisome proliferators.
Toxicol Lett. 2004; 149(1-3):37-41 [PubMed] Related Publications
Peroxisome proliferators (PPs) constitute a large and chemically diverse family of non-genotoxic rodent hepatocarcinogens that activate the PP-activated receptor alpha (PPARalpha). In order to investigate the hypothesis that PPs elicit their carcinogenic effects through the suppression of apoptosis, we established an in vitro assay for apoptosis using both primary rat hepatocytes and the FaO rat hepatoma cell line. Apoptosis was induced by transforming growth factor beta1 (TGFbeta1), the physiological negative regulator of liver growth. In this system, PPs could suppress both spontaneous and TGFbeta1-induced apoptosis. In order to understand the mechanisms of this regulation of apoptosis, we conducted microarray analysis followed by pathway-specific gene clustering in TGFbeta1-treated cells. After treatment, 76 genes were up-regulated and 185 were down-regulated more than 1.5-fold. Cluster analysis of up-regulated genes revealed three clusters, A-C. Cluster A (4h) was associated with 12% apoptosis and consisted of genes mainly of the cytoskeleton and extracellular matrix such as troponin and the proteoglycan SDC4. In cluster B (8h; 25% apoptosis), there were many pro- and anti-apoptotic genes such as XIAP, BAK1 and BAD, whereas at 16h (40% apoptosis) the regulated genes were mainly those of the cellular stress pathways such as the genes implicated in the activation of the transcription factor NFkappab. Genes found down-regulated in response to TGFbeta1 were mainly those associated with oxidative stress and several genes implicated in glutathione production and maintenance. Thus, TGFbeta1 may induce apoptosis via a down regulation of oxidant defence leading to the generation of reactive oxygen species. The ability of PPs to impact on these apoptosis pathways remains to be determined. To approach this question, we have developed a technique using laser capture microdissection of livers treated with the PP, clofibric acid coupled with gene expression array analysis. Results show that some of the key steps of the LCM process had an impact on the gene profiles generated. However, this did not preclude accurate determination of a PP-specific molecular signature. Thus, the choice of appropriate controls will ensure that meaningful gene expression analyses can be performed on tissue microdissected from the foci generated in clofibric acid treated livers. These data will allow the identification of specific genes that are regulated by PPs leading to changes in apoptosis and ultimately to tumours.

Toyota M, Kopecky KJ, Toyota MO, et al.
Methylation profiling in acute myeloid leukemia.
Blood. 2001; 97(9):2823-9 [PubMed] Related Publications
Aberrant methylation of multiple CpG islands has been described in acute myeloid leukemia (AML), but it is not known whether these are independent events or whether they reflect specific methylation defects in a subset of cases. To study this issue, the methylation status of 14 promoter-associated CpG islands was analyzed in 36 cases of AML previously characterized for estrogen-receptor methylation (ERM). Cases with methylation density of 10% or greater were considered positive. Seventeen cases (47%) were ERM(+) while 19 cases were ERM(-). Hypermethylation of any of the following, p15, p16, CACNA1G, MINT1, MINT2, MDR1, THBS1, and PTC1 (2 promoters), was relatively infrequent (6% to 31% of patients). For each of these CpG islands, the methylation density was positively correlated with ERM density (rank order correlation coefficients, 0.32-0.59; 2-tailed P < or = .058 for each gene). Hypermethylation of MYOD1, PITX2, GPR37, and SDC4 was frequently found in AML (47% to 64% of patients). For each of these genes as well, methylation density was positively correlated with ERM density (correlation coefficients 0.43 to 0.69, P < or = .0087 for each gene). MLH1 was unmethylated in all cases. Hypermethylation of p15, MDR1, and SDC4 correlated with reduced levels of expression. There was an inverse correlation between age and the number of genes methylated (P = .0030). It was concluded that CpG-island methylation in AML results from methylation defects in subsets of cases. These results have potential implications for the classification and prognosis of AML and for the identification of patients who may benefit from treatment with methylation inhibitors.

Dobra K, Andäng M, Syrokou A, et al.
Differentiation of mesothelioma cells is influenced by the expression of proteoglycans.
Exp Cell Res. 2000; 258(1):12-22 [PubMed] Related Publications
Malignant mesothelioma characteristically shows epithelial and/or sarcomatous morphology, this phenotypic differentiation being correlated to the prognosis. The present study was undertaken to see whether proteoglycan (PG) expression influences mesothelioma differentiation. To assess this hypothesis, we studied a mesothelioma model, where the cells were induced to differentiate into epithelial or fibroblast-like morphology, mimicking the biphasic growth of this sarcoma. Series of PGs were analyzed in parallel by semiquantitative reversed transcriptase polymerase chain reaction, showing increased expression of syndecan-2, syndecan-4, and hyaluronan synthase in the epithelial phenotype, whereas the fibroblast-like cells expressed more matrix PGs: versican, decorin, and biglycan. Western blotting confirms these differences and provides evidence of extensive shedding and rapid turnover of cell membrane PGs. Experimental down-regulation of the studied syndecans by antisense targeting resulted in a change in shape from polygonal to spindle-like morphology, while syndecan-1 and -4, but not syndecan-2, could be associated with cell aggregation, indicating distinct functions of different syndecans. The PG profile is thus closely associated with the morphology and biological behavior of tumor cells, mesotheliomas showing a different profile than true epithelial tumors.

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