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PubMed2002

cDNA array analysis of SPARC-modulated changes in glioma gene expression.

We have demonstrated that secreted protein acidic and rich in cysteine (SPARC) is highly expressed in human gliomas and it promotes glioma invasion and delays tumor growth in vitro and in vivo. cDNA array analyses were performed to determine whether SPARC, which interacts at the cell surface, has an impact on intracellular signaling and downstream gene expression changes, which might account for some of its effects on invasion and growth. Using a doxycycline (dox)-controlled gene expression system, two cDNA array analyses were performed using a parental U87T2 clone (-SPARC) transfected with the dox-controlled transactivator and a U87T2 parental-derived SPARC-transfected clone, A2b2 (+SPARC). Array analysis performed between the parental and the SPARC-transfected clone (-dox) identified 13 upregulated genes and 14 downregulated genes. With the exception of PAI-1 and MMP2, the identified genes are novel with respect to SPARC's mechanism of action. Array analysis performed using the SPARC-transfected clone ( +/- dox) identified 2 types of gene regulation; one reversible upon SPARC suppression, the other irreversible. Two of the SPARC-induced genes, BIGH3 (irreversible by dox) and PAI-1 (reversible by dox) were further studied in additional SPARC-transfected clones, human astrocytoma tissues, and human glioma cell lines by RT-PCR and Northern blot analyses. The results indicate that: (1) the array results were validated, (2) the dox regulation was validated, and (3) the differential expression identified by the array analyses was present between normal brain and in human astrocytoma tissues and cell lines. Therefore, we conclude that these cDNA array analyses provide candidate genes involved in SPARC-mediated effects on glioma cell cycle progression, signaling, and migration, and that SPARC may induce reversible and irreversible gene expression changes. Further investigation of these candidates may shed insights into SPARC's role in glioma cell proliferation and invasion, and potential use as a therapeutic target.

Anti-Bacterial Agents↗
PubMed1999

Expression of SPARC (secreted protein, acidic and rich in cysteine) in healing intestinal anastomoses and short bowel syndrome in rats.

Due to the proposed functions in soft tissue repair, we evaluated the spatial and temporal distribution of SPARC, a counteradhesive, matricellular glycoprotein in healing intestinal anastomoses and short bowel syndrome (SBS) in rats. Intestinal anastomoses were performed in the jejunum of male Wistar rats. SBS was induced by resecting 70% of the small bowel. In situ hybridization was performed to localize SPARC mRNA and immunohistochemical studies for locating the SPARC protein. The granulation tissue in the anastomotic area exhibited immunoreactivity for SPARC at all time points. The level of expression was maximal at seven to nine days. Endothelial cells of capillaries, smooth muscle cells, fibroblastic cells, and macrophages, as well as mesothelial cells on the serosal surface, were stained. The immunoreactivity was mostly intracellular. SPARC mRNA transcripts were localized to the edges of the anastomotic area at days 1 and 4 and on the newly formed granulation tissue later. The expression of SPARC mRNA was maximal at seven days and decreased thereafter. Both in normal controls and in SBS, SPARC was expressed in endothelial cells of submucosal capillaries and in smooth muscle cells but not in epithelium. Based on the restricted temporal and spatial distribution during the healing of intestinal anastomoses and in SBS we propose that SPARC plays a significant role in intestinal repair and adaptation.

Anastomosis, Surgical↗
PubMed2000

Induction of SC1 mRNA encoding a brain extracellular matrix glycoprotein related to SPARC following lesioning of the adult rat forebrain.

SC1 is an extracellular matrix (ECM) glycoprotein related to SPARC which exhibits anti-adhesive properties. ECM molecules are thought to play important roles in influencing cell shape, proliferation and migration during neurogenesis. Following localized injury to the adult rat forebrain, a biphasic induction of SC1 mRNA was apparent, namely a rapid, transient induction at 1 day post-lesion in cortical neurons which border the lesion site followed by a more prolonged induction in astrocytes which are proximal to the wound site. A similar SC1 induction pattern was observed in the hippocampus in response to the injury. SPARC mRNA exhibits a divergent pattern of induction because it is induced in mature blood vessels close to the lesion and in blood vessels which develop following the trauma. Thus mRNAs encoding the related ECM glycoproteins SC1 and SPARC are induced in different cell populations in the adult forebrain during the neural response to localized injury.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed2002

SPARC stimulates the synthesis of OPG/OCIF, MMP-2 and DNA in human periodontal ligament cells.

BACKGROUND: Osteonectin/secreted protein, acidic and rich in cysteine (SPARC) is expressed in periodontal ligaments. Therefore, a better understanding of the action of SPARC on periodontal ligament cells could help to elucidate remodelling and repair mechanisms in periodontal tissue. In the present study, we examined the effects of human platelet-derived SPARC (hp-SPARC) on the expressions of SPARC and osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF), alkaline phosphatase (ALPase) activity, matrix metalloproteinase-2 (MMP-2) production and DNA synthesis in cultures of human periodontal ligament (HPL) cells. METHODS: HPL cells at the sixth passage were exposed to hp-SPARC. The expression of OPG/OCIF and SPARC mRNAs was examined by Northern blot analysis. The protein levels for OPG/OCIF and MMP-2 were determined by Western blot analysis. ALPase activity was measured by the method of Bessey et al. DNA synthesis was estimated by incorporation of [3H] thymidine. RESULTS: Hp-SPARC enhanced OPG/OCIF synthesis at the protein and mRNA levels. Hp-SPARC also enhanced DNA and MMP-2 synthesis dose-dependently, but had little effect on ALPase activity and SPARC mRNA expression. CONCLUSION: SPARC may play a role in remodelling and repair of periodontal tissue by promoting proliferation and MMP-2 production. It may also regulate osteoclast formation through OPG/OCIF in periodontal ligament cells.

Alkaline Phosphatase↗
PubMed2000

Increased sensitivity to the stimulant effects of morphine conferred by anti-adhesive glycoprotein SPARC in amygdala.

Repeated administration of morphine substantially increases its locomotor-enhancing activity, a phenomenon termed locomotor sensitization. Here we show that secreted protein acidic and rich in cysteine (SPARC), an anti-adhesive glycoprotein present in the basolateral amygdala, contributes to the establishment of locomotor sensitization. The morphine-induced increase in SPARC levels in the basolateral amygdala persisted after morphine withdrawal and coincided with the duration of locomotor sensitization. Moreover, a single injection of morphine after SPARC infusion into the basolateral amygdala of previously uninjected mice substantially enhanced locomotor activity. Thus, SPARC may be an important element for establishing locomotor sensitization to morphine.

Amygdala↗
PubMed1996

SPARC is expressed in renal interstitial fibrosis and in renal vascular injury.

Tubulointerstitial inflammation and fibrosis are critical determinants for renal function and prognosis in a variety of human nephropathies. Yet, the pathophysiology of the injury remains obscure. We investigated the expression of SPARC (secreted protein acidic and rich in cysteine) by immunohistochemistry and in situ hybridization in experimental models characterized by tubulointerstitial fibrosis and matrix expansion in rats. SPARC is a secreted glycoprotein that has been demonstrated to affect cellular interaction with matrix proteins, modulate cell proliferation, bind to and/or inhibit growth factors such as PDGF and bFGF, and regulate angiogenesis. Interstitial expression of SPARC was most prominent in passive Heyman nephritis (PHN), chronic cyclosporine A (CsA) nephropathy, and the remnant kidney model and, to a lesser extent, in angiotensin II (Ang II)-infused animals. SPARC protein and mRNA were substantially increased at sites of tubulointerstitial fibrosis/matrix expansion. In the PHN model, SPARC protein was expressed by interstitial fibroblasts that also produced alpha-smooth muscle actin ("myofibroblasts") and correlated both temporally (r = 0.97) and spatially with sites of type I collagen deposition. Interstitial cell proliferation preceded the development of interstitial fibrosis, and maximal SPARC expression (d15) coincided with the initial decline in interstitial proliferation. In the Ang II-infusion model, which is characterized by arteriolopathy and tubulointerstitial injury, an increase in SPARC protein and mRNA was also seen in injured blood vessels. SPARC was shown to be expressed by vascular smooth muscle cells and also by cells in the adventitia of hypertrophied arteries. In summary, SPARC was transiently expressed by interstitial fibroblasts at sites of tubulointerstitial injury and fibrosis, and by smooth muscle cells and cells in the adventitia of injured arteries in the Ang II-model. In addition to its proposed role in extracellular matrix deposition. the antiproliferative properties of SPARC might contribute to the resolution of interstitial fibroblast proliferation in the PHN model.

Actins↗
PubMed1997

Manipulating the aggregation and oxidation of human SPARC in the cytoplasm of Escherichia coli.

Human SPARC (secreted protein acidic and rich in cysteine), an extracellular matrix protein containing 14 cysteine residues, was found to partition equally between soluble and insoluble cellular fractions when overexpressed in the Escherichia coli cytoplasm. While the growth temperature and medium pH had little effect on inclusion body formation, co-overproduction of the dnaKJ operon, but not of the groE operon, suppressed aggregation at the expense of intracellular accumulation. Although both forms of the protein were fully reduced in wild-type cells, 70% to 85% of soluble and insoluble SPARC could be converted into oxidized species in a thioredoxin reductase (trxB) null mutant following incubation on ice. Approximately 15% to 20% of SPARC exhibited the electrophoretic mobility of the biologically active protein. Overproduction of the dnaKJ operon in trxB cells decreased the formation of disulfide-bonded SPARC multimers in the aggregated material but not in its soluble counterpart. Our results suggest that the activity responsible for disulfide bond formation in trxB mutants acts at the post-translational level and is able to freely diffuse within inclusion bodies.

Amino Acid Sequence↗
PubMed1997

Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells.

Acquisition of invasive/metastatic potential is a key event in tumor progression. Cell surface glycoproteins and their respective matrix ligands have been implicated in this process. Recent evidence reveals that the secreted glycoprotein SPARC (secreted protein, acidic and rich in cysteine) is highly expressed in different malignant tissues. The present study reports that the suppression of SPARC expression by human melanoma cells using a SPARC antisense expression vector results in a significant decrease in the in vitro adhesive and invasive capacities of tumor cells, completely abolishing their in vivo tumorigenicity. This is the first evidence that SPARC plays a key role in human melanoma invasive-metastatic phenotype development.

Animals↗
PubMed2001

The expression of SPARC in adipose tissue and its increased plasma concentration in patients with coronary artery disease.

OBJECTIVE: Adipocytes secrete various cytokines and matrix proteins. Several of them precipitate in obesity-associated diseases, including atherosclerosis. In the current study, we have examined the expression of secreted protein, acidic and rich in cysteine (SPARC) in adipose tissue and its significance in obesity and coronary artery disease (CAD). RESEARCH METHODS AND PROCEDURES: The SPARC mRNA expressions both in vivo and in vitro were detected by Northern blot analysis. Plasma SPARC concentrations were measured by enzyme immunosorbent assay. First, we investigated the plasma SPARC levels of 88 unrelated adult Japanese subjects (62 men and 26 women; average age: [+/- SD] 50 +/- 12 years; body mass index [BMI]: 16 to 46 kg/m(2)). Additionally 31 subjects with CAD diagnosed by coronary angiography (20 men and 11 women) were also investigated. RESULTS: Human adipose tissues expressed abundant SPARC mRNA. SPARC expression in adipose tissues was upregulated in obese db/db mice. Markedly enhanced expression of SPARC mRNA was observed in 3T3-L1 fibroblasts during adipocyte differentiation. Consistent with these results, plasma SPARC levels proved a positive correlation with BMI in humans (r = 0.27; p < 0.01). Interestingly, plasma SPARC concentrations were significantly elevated in age- and BMI-matched subjects with CAD (p < 0.05). DISCUSSION: SPARC was expressed in adipose tissues and its expression was enhanced in obese mice. In human, plasma SPARC levels were elevated in obesity and CAD patients. This elevated SPARC may be involved in the progression of CAD.

Adipose Tissue↗
PubMed2006

Regulation of secreted protein acidic and rich in cysteine during adipose conversion and adipose tissue hyperplasia.

OBJECTIVE: To explore the regulation of secreted protein acidic and rich in cysteine (SPARC) expression and its role in adipose tissue. RESEARCH METHODS AND PROCEDURES: We studied the regulation of SPARC expression in transgenic mice expressing the human beta3 and alpha2 adrenergic receptors on a murine beta3 adrenergic receptor null background that became obese under a high-fat diet mainly as a result of adipose tissue hyperplasia. Furthermore, we analyzed its expression in human adipose tissue and its regulation during adipocyte differentiation. RESULTS: SPARC protein in adipose tissue was increased in obese transgenic mice compared with control mice, indicating that SPARC expression was associated with adipose tissue hyperplasia. Both SPARC mRNA and protein were detected in human adipose tissue. Comparing adipocytes and vascular stroma, we found that SPARC expression was mainly associated with the adipocyte fraction. Consistent with this, SPARC transcript increased during differentiation of human primary preadipocytes. 3T3-L1 preadipocytes showed an increase in SPARC expression in differentiated cells but with biphasic expression during the process. After induction in committed cells, SPARC mRNA and protein levels declined as differentiation began and returned to elevated levels in fully differentiated adipocytes. DISCUSSION: SPARC expression correlated with adipose tissue hyperplasia and adipogenesis. Therefore, SPARC seems to play a role in adipose tissue physiology as it is involved in growth and differentiation.

Adipocytes↗
PubMed1998

Advances in periodontal diagnosis. 10. Potential markers of bone resorption.

This paper describes the markers of bone resorption which might serve as potential markers for periodontal disease activity. It firstly describes the bone specific proteins which are involved in bone mineralisation and the role they play in this process. It then explains how they may pass into GCF and reviews those studies which have attempted to relate these factors to periodontal disease severity and activity. It next discusses the difficulties in isolating and detecting these factors in GCF and their possible use as markers for periodontal disease activity. As the final part in the series it lastly discusses the possible uses of predictive diagnostic tests of periodontal disease activity in dental practice.

Biomarkers↗
PubMed2003

Differential SPARC mRNA expression in Barrett's oesophagus.

Barrett's oesophagus (BE) is the precursor lesion to adenocarcinoma of the oesophagus. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that modulates cell adhesion and growth. Alterations in SPARC expression have been observed in a variety of solid tumours. The aim of this study was to assess the prevalence and timing of SPARC mRNA expression in Barrett's multistage disease and to investigate the impact of SPARC alterations on the development and progression of this disease. SPARC mRNA expression was measured using a quantitative real-time RT-PCR method in 108 specimens from 19 patients with BE without carcinoma, 20 patients with Barrett's-associated adenocarcinoma (EA), and a control group (CG) of 10 patients without evidence of gastro-oesophageal reflux disease. The median SPARC mRNA expression was significantly upregulated in BE tissues compared to paired normal oesophagus (NE) tissues for the BE group (P=0.004) and for the EA group (P<0.001). The SPARC mRNA expression was significantly higher in adenocarcinoma of the oesophagus compared to matching NE tissue and compared to Barrett's tissues in the EA group (P<0.001). Furthermore, SPARC expression values were significantly different between metaplastic and dysplastic Barrett's tissues (P=0.014). In histologically normal squamous oesophagus tissues obtained from carcinoma patients (EA group), the SPARC mRNA expression was significantly higher compared to NE mucosa from the BE group and the CG group (P=0.03). These findings suggest that the upregulation of SPARC mRNA expression is an early event in the development and progression of BE and EA, and that high SPARC expression may be a clinically useful biomarker for the detection of occult adenocarcinoma, and that a widespread 'field effect' is present in the NE of patients with oesophageal adenocarcinoma.

Adenocarcinoma↗
PubMed2005

Aberrant methylation of SPARC in human lung cancers.

SPARC (secreted protein acidic and rich in cysteine) is an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth. We investigated loss of expression of SPARC gene and promoter methylation in lung cancers and correlated the data with clinicopathological features. We observed loss of SPARC expression in 12 of 20 (60%) lung cancer cell lines. Treatment of expression-negative cell lines with a demethylating agent restored expression in all cases. Methylation frequencies of SPARC gene were 55% in 20 lung cancer cell lines. Primary tumours had methylation at a rate of 69% (119 of 173), while nonmalignant lung tissues (n=60) had very low rates (3%). In lung adenocarcinomas, SPARC methylation correlated with a negative prognosis (P=0.0021; relative risk 4.65, 95% confidence interval 1.75-12.35, multivariate Cox's proportional-hazard model). Immunostaining revealed protein expression in bronchial epithelium (weak intensity) and in juxtatumoral stromal tissues (strong intensity) accompanied by frequent loss in cancer cells that correlated with the presence of methylation (P<0.001). Our findings are of biological interest and potentially of clinical importance in human lung cancers.

Adenocarcinoma↗
PubMed2006

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells.

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.

Animals↗
PubMed1998

Differentially expressed genes in C6.9 glioma cells during vitamin D-induced cell death program.

C6.9 rat glioma cells undergo a cell death program when exposed to 1, 25-dihydroxyvitamin D3 (1,25-D3). As a global analytical approach, we have investigated gene expression in C6.9 engaged in this cell death program using differential screening of a rat brain cDNA library with probes derived from control and 1,25-D3-treated cells. Using this methodology we report the isolation of 61 differentially expressed cDNAs. Forty-seven cDNAs correspond to genes already characterized in rat cells or tissues. Seven cDNAs are homologous to yeast, mouse or human genes and seven are not related to known genes. Some of the characterized genes have been reported to be differentially expressed following induction of programmed cell death. These include PMP22/gas3, MGP and beta-tubulin. For the first time, we also show a cell death program induced up-regulation of the c-myc associated primary response gene CRP, and of the proteasome RN3 subunit and TCTP/mortalin genes. Another interesting feature of this 1,25-D3 induced-cell death program is the down-regulated expression of transcripts for the microtubule motor dynein heavy chain/MAP 1C and of the calcium-binding S100beta protein. Finally 15 upregulated cDNAs encode ribosomal proteins suggesting a possible involvement of the translational apparatus in this cell program. Alternatively, these ribosomal protein genes could be up-regulated in response to altered rates of cellular metabolism, as has been demonstrated for most of the other isolated genes which encode proteins involved in metabolic pathways. Thus, this study presents to our knowledge the first characterization of genes which are differentially expressed during a cell death program induced by 1, 25-D3. Therefore, this data provides new information on the fundamental mechanisms which participate in the antineoplastic effects of 1,25-D3 and on the machinery of a cell death program in a glioma cell line.

Animals↗