Reforma penzijskog sistema sa aspekta intenzivnog starenja stanovništva Srbije

Penzija predstavlja sredstvo socijalne zaštite u vidu novčane naknade koja štiti od rizika starosti, dok starenje stanovništva dovodi do dugoročnog uvećanja broja penzionera, što značajno utiče na stepen održivosti penzijskih sistema, dodatno opterećenih efektima svetske ekonomske krize, koja se polako transformiše, te iz dužničke prelazi u penzijsku krizu. Kao posledica takve tendencije predviđaju se veliki problemi u održavanju postojećih penzijskih sistema širom Evrope i drastično smanjivanje primanja najstarijih u narednim godinama. U Srbiji je, poslednjih decenija, prisutan trend intenzivnog starenja stanovništva, što veoma negativno utiče na održivost penzijskih sistema koji su finansirani po principu međugeneracijske solidarnosti. Shodno tome, predmet ovog rada je analiza održivosti i davanje preporuka koje će olakšati reformu penzionog sistema jer on predstavlja važan faktor ekonomske i socijalne stabilnosti

The role of Sonic Hedgehog signaling pathway in the regulation of SOX18 gene expression in HeLa cells, model system of cervical carcinoma

Sonic Hedgehog (SHH) signalni put ima važnu ulogu u procesima koji se odvijaju tokom embrionalnog razvića u kojima kontroliše proliferaciju i diferencijaciju ćelija i učestvuje u održavanju polarnosti tkiva. Poslednjih godina mnogobrojni literaturni podaci pokazuju da promena u regulaciji SHH signalnog puta dovodi do nastanka i progresije različitih vrsta tumora kod čoveka. SHH signalni put je povezan sa meduloblastomom, leukemijom, karcinomom bazalnih ćelija, tumorima pluća, prostate, pancreasa, dojke i jajnika. Takođe, povećana ekspresija komponenti SHH signalnog puta je primećena u premalignim lezijama i ćelijama karcinoma grlića materice. SOX18 gen pripada familiji SOX gena koji kodiraju transkripcione faktore uključene u kontrolu različitih procesa tokom embrionalnog razvića. SOX18 protein ima važnu ulogu u razviću vaskularnog sistema kao i u adultnoj neovaskularizaciji. Uloga SOX18 proteina u vaskularnom razviću otkrivena je na osnovu poremećaja u razvoju vaskularnog sistema koji su uočeni kod prirodnih mutanata miša i čoveka. Osim toga, kod adultnog organizma SOX18 protein učestvuje u regulaciji angiogeneze i limfangiogeneze kako u fiziološkim stanjima organizma, tako i tokom patofizioloških promena kao što su zarastanje rana i tumorska angiogeneza. Takođe, pokazano je da se inhibicijom SOX18 funkcije utiče na limfangiogenezu čime se sprečava metastaza ćelija tumora. Najnoviji podaci pokazuju da je ekspresija SOX18 gena, detektovana u ćelijama invazivnog karcinoma dojke i tumora jajnika, a nivo ekspresije je u direktnoj korelaciji sa stadijumom tumora i može predstavljati prognostički marker. Predmet istraživanja prikazanog u ovom radu je bila analiza uloge SHH signalnog puta u regulaciji ekspresije SOX18 gena u HeLa ćelijama, in vitro model sistemu karcinoma grlića materice. Prvo je analizirana uloga GLI regulatornih proteina, finalnih efektora SHH signalne kaskade, u regulaciji transkripcije SOX18 gena. Prikazani rezultati su pokazali da su GLI1 i GLI2 pozitivni regulatori promotorske aktivnosti SOX18 gena kao i da povećavaju endogenu ekspresiju SOX18 gena, dok GLI3 transkripcioni faktor nije uticao na aktivnost SOX18 promotorskog konstrukta niti na nivo endogene ekspresije SOX18 gena u HeLa ćelijama...The Sonic Hedgehog (SHH) signaling pathway plays important role in embrionic development directing cell proliferation and diferentiation and maintaing tissue polarity. In adults, this signaling pathway is rather suppressed. SHH signaling pathway has been associated with medulloblastoma, leukemia, basal cell carcinoma and lung, prostate, pancreatic, breast and ovarian cancers. In the last years, numerous data show that deregulation of SHH signaling pathway has been associated with onset and progression of various types of human cancer. It was shown that increased expression of HH-signaling molecules was seen in precancerous lesions and in cervical cancer. SOX18 gene is a member of SOX gene family that encodes transcription factors implicated in the control of various developmental processes. SOX18 protein plays important roles in vascular development and postnatal neovascularization. The functional importance of SOX18 protein in vascular development is revealed by the vascular defects caused by mutation in mice and humans. Also, in adults SOX18 is involved in the regulation of angiogenesis and lymphangiogenesis in physiological and pathophysiological condition such in wound healing or tumor growth. Furthermore, it has been reported that interfere with SOX18 function impairs tumor lymphangiogenesis which decreases the rate of cancer cell metastasis. In past two years, literature data show SOX18 expression in invasive ductual breast carcinoma and ovarian carcinoma and that level of expression correlates with poor prognosis suggesting that a SOX18 expression may serve as a prognostic marker. The aim of this study was to investigate the role of Sonic Hedgehog signaling pathway in the regulation of SOX18 gene expression in HeLa cells, in vitro model system of cervical cancer . We were analyzing the effect of GLI regulator proteins, final effectors of SHH signaling pathway, on transcriptional regulation of SOX18 gene expression. Presented results have shown that GLI1 and GLI2 are potent activators of SOX18 promoter activity as well as SOX18 expression in HeLa cells, while GLI3 had no effect..

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM

SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well. In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation

Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array) we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene

Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array) we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene

Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma

Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies

Involvement of ubiquitous and tale transcription factors, as well as liganded RXRα, in the regulation of human SOX2 gene expression in the NT2/D1 embryonal carcinoma cell line

SOX2 transkripcioni faktor ima ključnu ulogu u procesima embrionalnog razvića i predstavlja univerzalni marker pluripotentnih matičnih ćelija. S obzirom na funkcionalnu redundantnost i preklapajući profil ekspresije članova SOXB1 podgrupe tokom razvića, cilj ovog rada bio je da ispita potencijalne zajedničke aspekte regulacije ekspresije SOX2 i SOX3 gena. Naime, ispitivan je uticaj odabranih transkripcionih faktora na regulaciju ekspresije SOX2 gena u NT2/D1 ćelijskoj liniji. Analizirani su oni faktori za koje je prethodno pokazano da su uključeni u modulaciju aktivnosti humanog SOX3 gena. Rezultati ovih istraživanja ukazuju da opšti transkripcioni faktori (NF-Y, Sp1 i MAZ), članovi TALE familije proteina (Pbx1 i Meis1), kao i retinoičnom kiselinom aktiviran nuklearni receptor RXRα dovode do povećane ekspresije SOX2 proteina. Ispitivanje transkripcionih faktora uključenih u regulaciju ekspresije SOX gena je značajno za bolje razumevanje signalnih puteva koji su aktivni u pluripotentnim matičnim ćelijama.SOX2 is a key transcription factor in embryonic development representing a universal marker of pluripotent stem cells. Based on the functional redundancy and overlapping expression patterns of SOXB1 subgroup members during development, the goal of this study has been to analyze if some aspects of regulation of expression are preserved between human SOX2 and SOX3 genes. Thus, we have tested several transcription factors previously demonstrated to play roles in controlling SOX3 gene activity for potential participation in the regulation of SOX2 gene expression in NT2/D1 cells. Here we report on the activation of SOX2 expression by ubiquitous transcription factors (NF-Y, Sp1 and MAZ), TALE family members (Pbx1 and Meis1), as well as liganded RXRα. Elucidating components involved in the regulation of SOX gene expression represent a valuable contribution in unraveling the regulatory networks operating in pluripotent embryonic cells

Retinoic acid affects basic cellular processes and SOX2 and SOX18 expression in breast carcinoma cells

Genetic and molecular heterogeneity, together with intrinsic and acquired resistance to therapy, represent the major obstacles to the successful treatment of different types of breast carcinoma. Increasing evidence demonstrates that SOX transcription factors in breast carcinomas could act both as oncogenes and tumor suppressors and have been associated with tumor stage and grade, poor prognosis, and therapy resistance. Both SOX2 and SOX18 overexpression has been correlated with poor prognosis in breast carcinomas, and these genes are recognized as potential antitumor targets. Our aim was to evaluate the effect of retinoic acid (RA), a well-known cyto-differentiating agent, on breast carcinoma cells in vitro and to investigate the potential of RA treatment to modify the expression of SOX2 and SOX18 genes. By applying various experimental approaches, we evaluated the effect of RA on basic cellular processes in SK-BR-3 and MCF7 breast carcinoma cell lines. We have shown that RA inhibits cell growth, reduces the number of Ki-67 positive cells, and causes cell-cycle arrest. RA effect was more prominent in SK-BR-3 cell line that lacks SOX2 expression, including a higher decrease in cell viability, reduction in colony formation, and significant remodeling of cellular structure. We have shown that RA treatment led to the downregulation of SOX2 expression in MCF7 cells and to the reduction of SOX18 expression in both cell lines. By functional analysis, we showed that the anti-proliferative effect of RA in both cell lines was not based on the activity of stemness marker SOX2, pointing to a SOX2-independent mechanism of action. The ability of RA to reduce SOX2/SOX18 expression raises the possibility that these genes can be used as biomarkers to distinguish RA-responders from non-responders. Together, our study shows that the response of breast carcinoma cell lines to RA treatment may vary, highlighting that the development of RA-based therapy should consider differences in breast carcinoma subtypes

EP12.075 Detection rate of 22q11.2 microdeletion using strict diagnostic criteria

Background/Objectives: 22q11.2 microdeletion, detected in patients with 22q11.2 Deletion Syndrome (22q11.2DS), is the most common microdeletion syndrome in humans. 22q11.2DS has high risk for neurodevelopmental disorders and is associated with more than 180 malformations. Many investigations of the 22q11.2 microdeletion applying different recruitment criteria, revealed detection rate ranging from zero to 34.7%. Here we analyzed the frequency of 22q11.2 microdeletion among children having at least two out of five major characteristics of 22q11.2DS: congenital heart malformations (CHM), facial dysmorphism, immunological problems, palatal clefts and hypocalcemia. Methods: Children with clinical characteristics of 22q11.2DS were analyzed. Fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analysis were applied for detection of 22q11.2 microdeletion. Results: 22q11.2 microdeletion was detected in approximately 40% of children. CHM was found in all patients with 22q11.2 microdeletion. Dysmorphic facial features were present in about 45%, immunological problems in 30%, overt cleft palate in about 4% and hypocalcemia in approximately 60% of patients with 22q11.2 microdeletion. Conclusion: When at least two major features of 22q11.2DS are taking into consideration higher detection rate is obtained compared to one-feature criterion. These criteria could be considered by centers in low-income countries.Abstracts from the 55th European Society of Human Genetics (ESHG) Conference: e-Poster