Browsing by Subject "Survivin"
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- PublicationOpen AccessEffects of the isoflavone daidzein in Senegalese sole, Solea senegalensis: Modulation of the oestrogen receptor-β, apoptosis and enzymatic signalling pathways(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Sarasquete, Carmen; Úbeda Manzanaro, María; Ortiz Delgado, Juan B.Phytochemicals are widely present in the aquatic environment and they are derived from many anthropogenic activities. The isoflavone daidzein is a natural compound that is found in the soya products used as habitual constituents of aquafeeds. Nevertheless, this isoflavone possesses oestrogenic and apoptotic properties. The present study determined the effects of daidzein (at 20 mg/L) during the first month and a half of life (from 7 to 44 days post-hatching -dph-) of the flatfish Senegalese sole, Solea senegalensis, focusing at the metamorphosis. We have analysed different gene expression levels and immunohistochemical protein patterns implicated in some oestrogenic, apoptotic and enzymatic pathways. In general, the oestrogen receptor (ERβ) and stimulating apoptosis death receptor factor (Fas) transcript levels showed similar baseline patterns and transcriptional responses induced by daidzein. Both ERβ and Fas were up-regulated by this isoflavone at the pre-metamorphosis and metamorphosis, and they were down-regulated in post-metamorphosed stages. The expression pattern of the apoptotic effector caspase (Casp6) was exclusively up-regulated at the premetamorphic phase. The Birc5 transcripts (i.e. antiapoptosis, Survivin) were down-regulated by daidzein during certain metamorphic and post-metamorphosed stages. Besides, daidzein showed an up-regulating effect on both enzymatic complexes, the haemoprotein CYP1A and the acetylcholinesterase (AChE), except for a temporary AChE down-regulation in some postmetamorphosed stages. Immunostaining analysis only showed increased CYP1A signals in the liver of daidzein exposed fish. Overall, a majority of the transcriptional oestrogenic and apoptotic imbalances could be gradually and/or temporarily stabilised. Most controls and exposed larvae (70-80%) developed and grew following normal ontogenetic developmental patterns.
- PublicationOpen AccessMolecular markers predicting lymph node metastasis in early esophageal cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Plum, Patrick S.; Warnecke-Eberz, Ute; Dhaouadi, Oulfa; Alakus, Hakan; Drebber, Uta; Metzger, Ralf; Prenze, Klaus L.; Hölscher, Arnulf H.; Bollschweiler, Elfriedey. AIMS: The aim of this study was to identify molecular markers predicting depth of tumor infiltration and presence of lymph node metastasis in early esophageal cancer. METHODS: Between 1996 and 2004, 67 patients with pT1 esophagus cancer underwent esophagectomy. Resected tumors and lymph nodes were analyzed by immunohistochemistry for tissue infiltration, lymph node metastasis (LNM), micrometastasis and extracapsular lymph node infiltration (ELNI). We focused on MMP-2 (matrix-metalloproteinase-2), TIMP2 (tissue inhibitor of metalloproteinase-2), PIM-1 and survivin as the most promising marker candidates. The data was correlated with the patients’ long term followup (median follow-up time 11.4 years). RESULTS: We found 22 pT1a and 45 pT1b carcinomas. None of the mucosal carcinomas, but 58% (26 patients) of the submucosal carcinomas showed lymph node metastasis or micrometastasis. The rate of LNM positively correlated with the depth of tumor infiltration (23% LNM in sm1 tumors and 82% LNM in sm3 tumors). Low grade PIM-1 expression (<30%) was significantly associated with occurrence of LNM (p=0.034) while high expression TIMP-2 (>70%) were detected in submucosal tumors. Logistic regression analysis revealed PIM-1 and Grading G3 as independent risk factors for LNM (p<0.001). Survival of patients with micrometastasis was comparable to those with LNM (median survival: 5.05 years versus 5.52 years). Patients with ELNI had the worst prognosis (median survival: 1.7 years). CONCLUSIONS: PIM-1 is a promising marker for prediction of lymph node metastasis in early esophagus cancer. Extracapsular lymph node infiltration has an independent worse prognostic impact.
- PublicationOpen AccessP53, CD95, cathepsin and survivin pathways in Fuchs dystrophy and pseudophakic bullous keratopathy corneas(Murcia : F. Hernández, 2008) Szentmáry, Nora; Szende, Béla; Süveges, IldikoOur purpose was to elucidate the pathways of apoptosis of corneas with Fuchs’ dystrophy and pseudophakic bullous keratopathy. Sixteen corneal buttons (14 patients, median age 73 years) with Fuchs’ dystrophy, 13 with pseudophakic bullous keratopathy (PBK) (13 patients, median age 69 years) and 8 buttons (8 patients, median age 59 years) from enucleated eyes with chorioideal melanoma (controls) were analysed histologically. Immunohistochemical analysis was performed to investigate the expression of p21, p27, p63, survivin, CD95, cathepsin, bax, bcl-2 and Ki67. Positive immunohistochemical reactions were detected in epithelial cells of the corneas, but keratocytes and endothelial cells were not positive in any of the groups or stainings. The number of p27 and survivin positive epithelial cells was significantly lower (p=0.048 and 0.041) and the number of cathepsin positive epithelial cells was significantly higher (p=0.004) in Fuchs’ dystrophy corneas compared to controls. In pseudophakic bullous keratopathy, p21 and p27 positive epithelial cells were present in a significantly lower (p=0.02 and 0.005) number than in controls. We conclude that genetically programmed cell death is related to the p27, cathepsin and survivin pathways in Fuchs’ dystrophy and to the p21 and p27 pathways in pseudophakic bullous keratopathy.
- PublicationOpen AccessSurvivin - a universal tumor antigen(Murcia : F. Hernández, 2002) Andersen, M.H.; thor Straten, P.Tu m o r-associated antigens recognized by cellular effectors of the immune system are potential t a rgets for antigen-specific cancer immunotherapy. These antigens are classified as tissue (melanocy t e ) - s p e c i fic proteins, cancer-testis antigens (proteins expressed in normal testis and various cancers), tumorspecific peptides derived from mutations in tumor cells, and others. Clinical studies with peptides and proteins derived from these antigens have been initiated to study the effi c a cy of inducing specific cytotoxic T lymphocytes (CTL) responses in vivo. However, most of the peptide epitopes used in these vaccination trials are m e l a n o cy t e - s p e c i fic, and these peptides cannot be applied for tumors of non-melanocyte origin. Furthermore, the expression of most tumor antigens is heterogeneous among tumors from different patients and can even vary among metastases obtained from one patient. Immune selection of antigen loss variants may p r ove to be an additional obstacle for the clinical applicability of most of the known CTL epitopes. R e c e n t l y, a new tumor antigen, survivin, has been identified on the basis of spontaneous CTL responses in d i fferent cancer patients. Survivin is expressed in most human neoplasms, but not in normal, diff e r e n t i a t e d tissues. Importantly, dow n r egulation or loss of surviv i n would severely inflict the growth potential of the tumor cell. Since survivin is expressed by a variety of different tumors MHC-restricted survivin epitopes may serve as important and widely applicable targets for anti-cancer immunotherapeutic strategies.
- PublicationOpen AccessSurvivin overexpression in HCC and liver cirrhosis differentially correlates with p-STAT3 and E-cadherin(Murcia : F. Hernández, 2010) Peroukides, Stavros; Bravou, Vasiliki; Alexopoulos, Alexandros; Varakis, John; Kalofonos, Haralabos; Papadaki, HelenSurvivin, a member of the family of inhibitorof apoptosis proteins, functions as a key regulator ofapoptosis and cell proliferation. Overexpression ofsurvivin has been implicated in several human cancers,including human hepatocellular carcinoma (HCC).Although several factors have been shown in vitrotoupregulate survivin expression in cancer cells, the invivoregulators of survivin in human hepato-carcinogenesis are largely unknown. We studied byimmunohistochemistry the protein expression ofsurvivin in relation to cyclin D1, phosphorylated signaltransducer and activator of transcription 3 (p-STAT3), ß-catenin, E-cadherin and phosphorylated-Akt (p-Akt) in69 cases of HCC and adjacent liver cirrhosis. Survivinwas expressed in 63/69 (91.3%) cases of HCC and in40/47 (85.1%) cases of liver cirrhosis. Survivinlocalization in HCC was exclusively nuclear, whileintense cytoplasmic and low nuclear expression ofsurvivin was observed in cases of cirrhosis. Survivinexpression in HCC correlated significantly with lowgrade tumors, expression of cyclin D1 and p-STAT3.Expression of survivin in liver cirrhosis correlated withdownregulation of E-cadherin expression. There was nosignificant correlation of survivin with ß-catenin or p-Akt in HCC or liver cirrhosis. In conclusion, we showedan association of nuclear survivin with welldifferentiated HCC, as well as with the expression of thecell cycle regulator cyclin D1. Activation of STAT3 andloss of E-cadherin but not ß-catenin or Akt pathwaysseem to be implicated in survivin upregulation in HCCand liver cirrhosis.
- PublicationOpen AccessSurvivin phosphorylation and M-phase promoting factor in oral carcinogenesis(Murcia : F. Hernández, 2007) Pannone, G.; Bufo, P.; Serpico, R.; Rubini, C.; Zamparese, R.; Corsi, F.; Pedicillo, M.C.; Staibano, S.; De Rosa, G.; Lo Muzio, L.Survivin is a recently described inhibitor of apoptosis and mitotic regulator which is selectively overexpressed in human tumors. Its expression rate is predictive of disease progression, early recurrences and resistance to therapy. Up-regulation of survivin in oral pre-malignant lesions (OPL) and in oral squamous cell carcinoma (OSCC) has already been demonstrated in previous studies. A critical step for activation of survivin has been identified in the phosphorylation on Thr34 by the main mitotic kinase p34cdc2–cyclin B1. The aim of this work was to investigate the relationship between survivin, its phosphorylated active form (p-survivin) and M-phase promoting factor (MPF), p34cdc2-cyclin B1 in oral carcinogenesis. 32 OSCCs and 17 OPLs from surgical specimens were studied for cyclin B1, psurvivin, survivin, and p34cdc2 expression by immunohistochemistry. All cases of OSCC expressed survivin and its expression rate was correlated to psurvivin levels (P<0.05). Cyclin B1 was positive in 80% of cases, while p-34cdc2 was over-expressed in all OSCCs. All OPLs associated with OSCC expressed survivin and its levels were correlated to p-survivin levels (P<0.05). Cyclin B1 was positive in 70% of cases, while p-34cdc2 was positive in all OPLs. In conclusion, this study demonstrated that MPF, survivin and psurvivin are expressed during early and late phase of oral carcinogenesis. MPF proteins, which are co-expressed on mitotic apparatus, could represent a potential target for therapies based on manipulation of survivin phosphorylation, which would induce apoptosis in cancer cells.
- PublicationOpen AccessThe combination of strong immunohistochemical mtTFA expression and a high survivin index predicts a shorter diseasespecific survival in pancreatic ductal adenocarcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Kimura, Tomoko; Kitada, Shohei; Uramoto, Hidetaka; Zhi, Li; Kawatsu, Yuichiro; Takeda, Toru; Horie, Seichi; Nabeshima, Atsunori; Noguchi, Hirotsugu; Sasaguri, Yasuyuki; Izumi, Hiroto; Kohno, Kimitoshi; Yamada, SohsukeMitochondrial transcription factor A (mtTFA) plays a crucial role in both the transcription and maintenance of mitochondrial DNA. A high expression of mtTFA has been demonstrated in several solid tumors, and is closely associated with cancer cell survival/apoptosis and growth. However, its expression pattern in pancreatic ductal adenocarcinoma (PAC) remains to be elucidated. Additionally, our groups have recently revealed that a subset of apoptosis-related genes is strongly regulated by mtTFA, and that two putative mtTFA binding sites are present in the promoter region of the survivin gene, which is a member of the inhibitorof-apoptosis protein family. We therefore investigated the correlation of the immunohistochemical mtTFA expression and the survivin index with various clinicopathological variables and the prognosis, using 70 paraffin-embedded tumor samples from patients with surgically-resected PAC. The mtTFA expression or survivin index was considered to be strong or high when ≥30% or 10% of the PAC cells showed positive staining, respectively. Strong mtTFA expression and/or a high survivin index was revealed to have a significant relationship to a pathologically high tumor grading and advanced tumor stage. Moreover, mtTFA showed significantly high co-expression with survivin. Univariate and multivariate analyses demonstrated that both the strong mtTFA expression and high survivin index groups had significantly shorter survival rates, especially within the first two years postoperatively. The combination of strong mtTFA expression and a high survivin index may predict a poor prognosis in patients with PAC, and these new biomarkers might offer useful information for the early clinical management.
- PublicationOpen AccessThe emerging role of exosomes in survivin secretion(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Khan, Salma; Ferguson Bennit, Heather; Wall, Nathan R.The tumor microenvironment plays an integral part in the biology of cancer, participating in tumor initiation, progression, and response to therapy. Factors released by tumor cells themselves contribute in creating an environment mostly favorable but sometimes detrimental to the tumor. Survivin, one of the key members of the inhibitor of apoptosis (IAP) family of proteins, has been shown in the cytoplasm, mitochondria, nucleus, and most recently in the extracellular space, transported via small membrane bound vesicles called exosomes. Exosomes are secreted from hematopoietic, non-hematopoietic, tumor, and nontumor cells, shuttling essential molecules such as proteins, RNAs, and microRNAs, all believed to be important for cell-cell and cell-extracellular communication. In this review, we discuss exosomal Survivin and its role in modifying the tumor microenvironment.