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BCL11B Is Up-Regulated by EWS/FLI and Contributes to the Transformed Phenotype in Ewing Sarcoma  [PDF]
Elizabeth T. Wiles, Bianca Lui-Sargent, Russell Bell, Stephen L. Lessnick
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059369
Abstract: The EWS/FLI translocation product is the causative oncogene in Ewing sarcoma and acts as an aberrant transcription factor. EWS/FLI dysregulates gene expression during tumorigenesis by abnormally activating or repressing genes. The expression levels of thousands of genes are affected in Ewing sarcoma, however, it is unknown which of these genes contribute to the transformed phenotype. Here we characterize BCL11B as an up-regulated EWS/FLI target that is necessary for the maintenance of transformation in patient derived Ewing sarcoma cells lines. BCL11B, a zinc finger transcription factor, acts as a transcriptional repressor in Ewing’s sarcoma and contributes to the EWS/FLI repressed gene signature. BCL11B repressive activity is mediated by the NuRD co-repressor complex. We further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, limits the transformation capacity of Ewing sarcoma cells. These data define a new pathway downstream of EWS/FLI required for oncogenic maintenance in Ewing sarcoma.
Following Inhibition of BCL-2 by Antisense Oligonucleotides Compensatory Suppression of Apoptosis Involves the Direct Signal Transduction Pathway of LNCaP Cells  [PDF]
Marvin Rubenstein, Courtney M. P. Hollowell, Patrick Guinan
Open Journal of Apoptosis (OJApo) , 2015, DOI: 10.4236/ojapo.2015.41001
Abstract: Previously we have shown that when LNCaP cells are treated with antisense oligonucleotides (oligos) directed against BCL-2, compensatory changes in non-targeted genes take place in attempts to restore apoptosis and promote tumor aggressiveness. In addition to the inhibition of BCL-2, we find that the apoptosis promoter caspase-3 activity is suppressed, the transcription activity of STAT-3 is enhanced, while other regulators (bax, clusterin, AKT-1) associated with mitochondrial regulated apoptosis and caspase cascade are either unchanged or undetectable. We now evaluate proteins associated with the second pathway of apoptosis activation mediated by direct signal transduction involving fas, fas-ligand (a tumor necrosis factor-like cell surface receptor aka CD95), as well as the similar programmed death cell surface receptor (PD-1) and its respective ligand (PD-1L). This study evaluates the growth inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against BCL-2 [the second binding site was directed against the epidermal growth factor receptor (EGFR)]; and employing RT-PCR. The expression of these four proteins was evaluated. Expression of fas-ligand, PD-1 and PD-L1 were all significantly enhanced, whereas fas itself was undetectable. This suggests that in addition to pathways associated with the mitochondrial pathway of apoptosis, compensatory changes occur in the direct signal transduction pathway of this process. In addition to alterations in androgen sensitivity, growth factor expression and oncogene expression, these data suggest that suppressive BCL-2 therapy involves multiple pathways, including those involved with immune targeting and cytotoxicity and must be taken into account to make gene therapy more efficacious.
Expression of Bcl2 proto-oncogene in primary tumors of the central nervous system.  [cached]
Tyagi D,Sharma B,Gupta S,Kaul D
Neurology India , 2002,
Abstract: The present study was addressed to find out the expression of Bcl2 proto-oncogene in tumor tissues derived from 25 patients with primary central nervous system tumors. Brain parenchyma in 8 cases, with deeply located tumor, was also examined for Bcl2 expression which served as control. Both benign and malignant tumors (confirmed by histopathological examination) expressed Bcl2 gene product. Tumors exhibited 2-6 fold increase in Bcl2 expression as compared to the normal parenchyma adjacent to some of these tumors studied. However, no correlation was found between the histopathological types of tumor, glial fibrillary acidic protein positivity and degree of Bcl2 expression. Based on this study, we propose that the overexpression of Bcl2 gene product found in primary CNS tumors may be an important molecular event which is known to make the various types of tumor resistant to chemotherapy or radiotherapy.
Electroporation increases antitumoral efficacy of the bcl-2 antisense G3139 and chemotherapy in a human melanoma xenograft
Enrico P Spugnini, Annamaria Biroccio, Roberta De Mori, Marco Scarsella, Carmen D'Angelo, Alfonso Baldi, Carlo Leonetti
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-125
Abstract: Melanoma-bearing nude mice were treated i.v. with G3139 and/or cisplatin (DDP) followed by the application of trains of electric pulses to tumors. Western blot, immunohistochemistry and real-time PCR were performed to analyze protein and mRNA expression. The effect of electroporation on muscles was determined by histology, while tumor apoptosis and the proliferation index were analyzed by immunohistochemistry. Antisense oligodeoxynucleotides tumor accumulation was measured by FACS and confocal microscopy.The G3139/Electroporation combined therapy produced a significant inhibition of tumor growth (TWI, more than 50%) accompanied by a marked tumor re-growth delay (TRD, about 20 days). The efficacy of this treatment was due to the higher G3139 uptake in tumor cells which led to a marked down-regulation of bcl-2 protein expression. Moreover, the G3139/EP combination treatment resulted in an enhanced apoptotic index and a decreased proliferation rate of tumors. Finally, an increased tumor response was observed after treatment with the triple combination G3139/DDP/EP, showing a TWI of about 75% and TRD of 30 days.These results demonstrate that electroporation is an effective strategy to improve the delivery of antisense oligodeoxynucleotides within tumor cells in vivo and it may be instrumental in optimizing the response of melanoma to chemotherapy. The high response rate observed in this study suggest to apply this strategy for the treatment of melanoma patients.There is currently great interest in the use of oligodeoxynucleotides antisense (ASOs), siRNA and aptamers for the treatment of different diseases, including cancer. Phosphorothioate ASOs are the most widely explored first-generation analogues [1] and preclinical studies have demonstrated that these agents are able to reduce target gene expression and have also shown activity against a wide variety of tumors, both alone and in combination with antineoplastic drugs [2]. Phosphorothioate ASOs have a greater bioavai
Bcl-2 expression is altered with ovarian tumor progression: an immunohistochemical evaluation
Nicole S Anderson, Leslie Turner, Sandra Livingston, Ren Chen, Santo V Nicosia, Patricia A Kruk
Journal of Ovarian Research , 2009, DOI: 10.1186/1757-2215-2-16
Abstract: Ovarian tissue sections were classified as normal (n = 2), benign (n = 17) or cancerous (n = 28) and immunohistochemically stained for Bcl-2. Bcl-2 expression was assessed according to cellular localization, extent, and intensity of staining. The number of lymphocyte nests as well as the number of lymphocytes within these nests was counted.While Bcl-2 staining remained cytoplasmic, both percent and intensity of epithelial and stromal Bcl-2 staining decreased with tumor progression. Further, the number of lymphocyte nests dramatically increased with tumor progression.The data suggest alterations in Bcl-2 expression and lymphocyte infiltration correlate with epithelial ovarian cancer progression. Consequently, Bcl-2 expression and lymphocyte status may be important for prognostic outcome or useful targets for therapeutic intervention.Ovarian cancer (OC) currently ranks 5th in cancer related deaths among women in the United States [1] in spite of advances in treatment. Despite an overall OC survival rate of 45%, the five year survival rate for women diagnosed with OC in its early stages is 94%, however these women only make up 19% of reported OC cases [2]. This poor prognosis is, in part, due to a lack of symptoms at early stages as well as lack of a screening marker available to the general public. The ovarian surface epithelium is generally believed to be the origin for the majority of epithelial ovarian cancer cases [3], though current reports of a fallopian tube origin for ovarian cancer have emerged [4,5]. Consequently, the etiology of ovarian cancer is still poorly understood.A basement membrane consisting mainly of collagenous connective tissue separates the ovarian surface epithelium (OSE), a modified mesothelium, from underlying ovarian stromal tissue [6]. The OSE and stroma both synthesize and secrete components that contribute to deposition of the basement membrane during postovulatory repair [7]. Normal ovarian stroma also produces an array of growth factor
Acetylation of the Proto-Oncogene EVI1 Abrogates Bcl-xL Promoter Binding and Induces Apoptosis  [PDF]
Anjan Kumar Pradhan,Alok Das Mohapatra,Kasturi Bala Nayak,Soumen Chakraborty
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025370
Abstract: EVI1 (Ecotropic Viral Integration site I), which was originally identified as a myeloid transforming gene by means of retroviral insertional mutagenesis in mouse leukemia, encodes a nuclear DNA binding zinc finger protein. The presence of zinc fingers that are able to bind to specific sequences of DNA suggests that EVI1 is a transcriptional regulator; however, except a few, target genes of EVI1 are poorly functionally identified thus far. In this study we provide evidence that EVI1 directly induces the expression of Bcl-xL through the first set of zinc finger and thereby inhibits apoptosis. ChIP analysis showed that EVI1 binds to the Bcl-xL promoter in HT-29 cells, a colon carcinoma cell line, which expresses EVI1. The observation is also supported by the fact that EVI1 siRNA treated HT-29 cells, shows a down regulation of Bcl-xL expression and that over expression of EVI1 results in the induction of the Bcl-xL reporter construct. A set of EVI1 positive chronic myeloid leukemia (CML) samples also showed higher Bcl-xL expression with respect to EVI1 negative samples. Interestingly, co-expression of EVI1 with wild type, but not with dominant-negative form of PCAF, abolishes the effect of EVI1 on Bcl-xL, indicating that acetylation of EVI1 abrogates its ability not only to bind Bcl-xL promoter but also alleviate Bcl-xL activity. Finally we have shown that EVI1 expression regulates apoptosis in HT-29 cells, which is abrogated when HT-29 cells are transfected with EVI1 siRNA or PCAF. The result for the first time shows a direct pathway by which EVI1 can protect cells from apoptosis and also demonstrates that the pathway can be reversed when EVI1 is acetylated.
Reversing Multidrug Resistance in Caco-2 by Silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL Using Liposomal Antisense Oligonucleotides  [PDF]
Yu-Li Lo, Yu Liu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090180
Abstract: Multidrug resistance (MDR) is a major impediment to chemotherapy. In the present study, we designed antisense oligonucleotides (ASOs) against MDR1, MDR-associated protein (MRP)1, MRP2, and/or BCL-2/BCL-xL to reverse MDR transporters and induce apoptosis, respectively. The cationic liposomes (100 nm) composed of N-[1-(2,3-dioleyloxy)propyl]-n,n,n-trime?thylammoniumchloride and dioleoyl phosphotidylethanolamine core surrounded by a polyethylene glycol (PEG) shell were prepared to carry ASOs and/or epirubicin, an antineoplastic agent. We aimed to simultaneously suppress efflux pumps, provoke apoptosis, and enhance the chemosensitivity of human colon adenocarcinoma Caco-2 cells to epirubicin. We evaluated encapsulation efficiency, particle size, cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of these formulations. We found that PEGylated liposomal ASOs significantly reduced Caco-2 cell viability and thus intensified epirubicin-mediated apoptosis. These formulations also decreased the MDR1 promoter activity levels and enhanced the intracellular retention of epirubicin in Caco-2 cells. Epirubicin and ASOs in PEGylated liposomes remarkably decreased mRNA expression levels of human MDR1, MRP1, MRP2, and BCL-2. The combined treatments all significantly increased the mRNA expressions of p53 and BAX, and activity levels of caspase-3, -8, and -9. The formulation of epirubicin and ASOs targeting both pump resistance of MDR1, MRP1, and MRP2 and nonpump resistance of BCL-2/BCL-xL demonstrated more superior effect to all the other formulations used in this study. Our results provide a novel insight into the mechanisms by which PEGylated liposomal ASOs against both resistance types act as activators to epirubicin-induced apoptosis through suppressing MDR1, MRP1, and MRP2, as well as triggering intrinsic mitochondrial and extrinsic death receptor pathways. The complicated regulation of MDR highlights the necessity for a multifunctional approach using an effective delivery system, such as PEGylated liposomes, to carry epirubicin and ASOs as a potent nanomedicine for improving the clinical efficacy of chemotherapy.
抗凋亡的“原癌基因”Bcl-2实为抗癌基因
The antiapoptotic “oncogene” Bcl-2 is a de facto tumor suppressor
 [PDF]

付大富,梁媛,覃君慧,克祯彧,王瑞安
- , 2016,
Abstract: 长期以来,细胞凋亡减少被认为是肿瘤发生的重要原因和机制,具有抗凋亡作用的基因被认为是癌基因。Bcl-2是在滤泡性B细胞淋巴瘤中分离出来的具有很强抗凋亡作用的基因,是这类癌基因的原型。吊诡的是,Bcl-2对肿瘤的发生和发展有很强的抑制作用。这种作用包括三个方面:①在培养细胞,Bcl-2的过表达可抑制细胞的生长和集落的形成;②在转基因动物,Bcl-2的过表达可抑制化学致癌物和其他癌基因诱发的肿瘤发生和生长;③在多种肿瘤,Bcl-2的过表达与患者的预后好相关。Bcl-2的这种生物学作用提示我们应该对癌基
The antiapoptotic genes have long been taken as a type of oncogenes, since reduced cell death has beenregarded as an important mechanism of oncogenesis and cancer development. Bcl-2 is a prototype of the antiapoptoticgenes originally isolated from the follicular B cell lymphoma. Paradoxically, Bcl-2 has a strong tumor suppressing effect,which is showed in the following aspects: ① overexpressed Bcl-2 inhibits the focus formation and cell growth ex vivo;②overexpressed Bcl-2 inhibits carcinogenesis induced by chemical carcinogens and other oncogenes in transgenicanimal studies; ③the overexpression is positively associated with favorable clinical outcomes of cancer patients. Theseparadoxical functions of Bcl-2 drive us to reconsider the concepts of oncogenes and tumor suppressor genes. We suggestputting Bcl-2 and other antiapoptotic genes in the tumor suppressor genes, instead of oncogenes. Further, instead ofblocking Bcl-2, a reverse strategy of mimicking the effects of Bcl-2 can be adopted in the cancer treatment
3A Study of the Significance of Apoptosis and its Association with Abnormalities in Expression of BCL-2 Proto-Oncogene in Benign Nodular Hyperplasia of Prostate
Srikumar Chakravarthi,Linda Tjoa Husin,P.M. Thani,Nadeem Irfan Bukhari
Research Journal of Biological Sciences , 2012,
Abstract: Benign Prostatic Hyperplasia (BPH) is an enlargement of the prostate gland caused by an increase in the number of glandular units. Apoptosis is a programmed cell death necessary for the regulation of the size of organs in adult life. Disruption of apoptotic pathways has been suggested as an important regulatory mechanism in BPH. A high level of the BCL-2 protein suppresses apoptosis by preventing the activation of the enzymes that carry out the process. In this study, an attempt was made to observe the abnormal expression of BCL-2 protein in BPH tissues in paraffin sections and to demonstrate the disruption of apoptotic pathways in BPH. Prostatic tissue from 30 patients with BPH and no prior prostatic carcinoma were obtained by transurethral resection of prostate procedure. Apoptotic index was compared in the H and E sections. Expression of BCL-2 was analyzed by immunohistochemistry and evaluated. Apoptotic index in BPH tissues was found to be twice lower than that of normal tissues. Wilcoxon signed rank test was employed and the p-value proved that the results were highly significant (p<0.01). This data supported the research hypothesis that apoptotic index is decreased in benign prostatic hyperplasia. Out of 30 tissue samples, 20 (67%) shown positivity for BCL-2 expression. Kendall’s Tau-B test was applied and the result showed negative correlation between the intensity of BCL-2 expression and apoptosis, however not significantly. This proves, the theory that BCL-2 regulates individual cell death up to a certain extent.
miR-127 Regulates Cell Proliferation and Senescence by Targeting BCL6  [PDF]
Jingwen Chen, Miao Wang, Mingzhou Guo, Yuntao Xie, Yu-Sheng Cong
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080266
Abstract: Cellular senescence occurs as a response to extracellular and intracellular stresses and contributes to aging and age-related pathologies. Emerging evidence suggests that cellular senescence also acts as a potent tumor suppression mechanism that prevents the oncogenic transformation of primary human cells. Recent reports have indicated that miRNAsact as key modulators of cellular senescence by targeting critical regulators of the senescence pathways. We previously reported that miR-127 is up-regulated in senescent fibroblasts. In this report, we identified miR-127 as a novel regulator of cellular senescence that directly targets BCL6. We further showed that miR-127 is down-regulated in breast cancer tissuesand that this down-regulation is associated with up-regulation of BCL6. Over-expression of miR-127 or depletion of BCL6 inhibits breast cancer cell proliferation. Our data suggest that miR-127 may function as a tumor suppressor that modulates the oncogene BCL6.
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