The Experts below are selected from a list of 2103 Experts worldwide ranked by ideXlab platform
Yang Sun - One of the best experts on this subject based on the ideXlab platform.
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SBF-1 preferentially inhibits growth of highly malignant human Liposarcoma Cells.
Journal of pharmacological sciences, 2018Co-Authors: W. Chen, Xuelong Qian, Wei Jin, Yunlong Shan, Xianying Fang, Yang Sun, Qiong LuoAbstract:Abstract Frequent local recurrence and metastasis are generally involved in human Liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human Liposarcoma SW872-S Cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced Cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S Cells, indicating that OSBP may be involved in malignant Liposarcoma Cell survival. Cancer Cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S Cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S Cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human Liposarcoma.
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SBF-1 preferentially inhibits growth of highly malignant human Liposarcoma Cells
Elsevier, 2018Co-Authors: W. Chen, Xuelong Qian, Wei Jin, Yunlong Shan, Xianying Fang, Yang Sun, Qiong LuoAbstract:Frequent local recurrence and metastasis are generally involved in human Liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human Liposarcoma SW872-S Cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced Cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S Cells, indicating that OSBP may be involved in malignant Liposarcoma Cell survival. Cancer Cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S Cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S Cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human Liposarcoma. Keywords: SBF-1, Malignant Liposarcoma, SW872-
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high expression of sarcoplasmic endoplasmic reticulum ca2 atpase 2b blocks Cell differentiation in human Liposarcoma Cells
Life Sciences, 2014Co-Authors: Lu Wang, Yang Sun, Yang Yang, Yongqian Shu, Yan ShenAbstract:Abstract Aims We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca 2 + -ATPase 2 (SERCA2) was related to the malignant degree of different types of human Liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human Liposarcoma Cell line SW872 Cells. Main methods SW872 Cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extraCellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively. Key findings High expression of SERCA2b promoted Cell proliferation and blocked the differentiation potential of SW872 Cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes. Significance The results revealed a novel role of SERCA2b in facilitating the blockade of human Liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human Liposarcoma.
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High expression of sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase 2b blocks Cell differentiation in human Liposarcoma Cells
Life sciences, 2014Co-Authors: Lu Wang, Yang Sun, Yang Yang, Yongqian Shu, Yan ShenAbstract:Abstract Aims We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca 2 + -ATPase 2 (SERCA2) was related to the malignant degree of different types of human Liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human Liposarcoma Cell line SW872 Cells. Main methods SW872 Cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extraCellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively. Key findings High expression of SERCA2b promoted Cell proliferation and blocked the differentiation potential of SW872 Cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes. Significance The results revealed a novel role of SERCA2b in facilitating the blockade of human Liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human Liposarcoma.
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Targeting Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase 2 by Curcumin Induces ER Stress-Associated Apoptosis for Treating Human Liposarcoma
Molecular cancer therapeutics, 2011Co-Authors: Lu Wang, Yang Sun, Yan Shen, Lingxian Wang, Ran Song, Yongqian ShuAbstract:Human Liposarcoma is the most common soft tissue sarcoma. There is no effective therapy so far except for surgery. In this study, we report for the first time that curcumin induces endoplasmic reticulum (ER) stress in human Liposarcoma Cells via interacting with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2). Curcumin dose-dependently inhibited the Cell survival of human Liposarcoma Cell line SW872 Cells, but did not affect that of human normal adipose-derived Cells. Curcumin-mediated ER stress via inhibiting the activity of SERCA2 caused increasing expressions of CHOP and its transcription target death receptor 5 (TRAIL-R2), leading to a caspase-3 and caspase-8 cascade-dependent apoptosis in SW872 Cells in vitro and in vivo . Moreover, 70% of human Liposarcoma tissues showed an elevated SERCA2 expression compared with normal adipose tissues. Curcumin dose-dependently inhibited the activity of SERCA2, and the interaction of molecular docking and colocalization in ER of curcumin with SERCA2 were further observed. These findings suggest that curcumin may serve as a potent agent for curing human Liposarcoma via targeting SERCA2. Mol Cancer Ther; 10(3); 461–71. ©2011 AACR .
Yan Shen - One of the best experts on this subject based on the ideXlab platform.
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TP53INP2-related basal autophagy is involved in the growth and malignant progression in human Liposarcoma Cells
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2017Co-Authors: Wenwen Xue, Juan Pang, Yiwei Meng, Yan ShenAbstract:Abstract Background Understanding the function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancers. Here, we studied the contribution of basal autophagy in human Liposarcoma. Methods The levels of basal autophagy were analyzed by measuring autophagy-related protein expression and autophagosome formation. TP53INP2 expression was determined by real-time PCR, western blot and tissue microarray. Genetic inhibition or overexpression of TP53INP2 was performed to examine its effects on autophagic activity and Cell growth. Results Compared with human Liposarcoma Cell line SW872, low level of basal autophagy were present in SW872-S Cells with high malignancy. Moreover, a decrease of TP53INP2 expression was found accompanying Liposarcoma malignant progression in Cell lines and primary tissues. TP53INP2 expression was required for autophagic activity in Liposarcoma Cells. Autophagy inhibition with chloroquine suppressed the growth of Liposarcoma Cells. TP53INP2-related basal autophagy rendered Liposarcoma Cells to be more resistant to bortezomib-induced inhibition of Cell growth. Conclusions The results reveal the association of TP53INP2-related basal autophagy with Cell growth and malignant progression of human Liposarcoma, which helps re-evaluate targeting autophagy for cancer therapy, and suggest that TP53INP2 expression might be used as a prognostic marker to predict human Liposarcoma malignancies.
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high expression of sarcoplasmic endoplasmic reticulum ca2 atpase 2b blocks Cell differentiation in human Liposarcoma Cells
Life Sciences, 2014Co-Authors: Lu Wang, Yang Sun, Yang Yang, Yongqian Shu, Yan ShenAbstract:Abstract Aims We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca 2 + -ATPase 2 (SERCA2) was related to the malignant degree of different types of human Liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human Liposarcoma Cell line SW872 Cells. Main methods SW872 Cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extraCellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively. Key findings High expression of SERCA2b promoted Cell proliferation and blocked the differentiation potential of SW872 Cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes. Significance The results revealed a novel role of SERCA2b in facilitating the blockade of human Liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human Liposarcoma.
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High expression of sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase 2b blocks Cell differentiation in human Liposarcoma Cells
Life sciences, 2014Co-Authors: Lu Wang, Yang Sun, Yang Yang, Yongqian Shu, Yan ShenAbstract:Abstract Aims We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca 2 + -ATPase 2 (SERCA2) was related to the malignant degree of different types of human Liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human Liposarcoma Cell line SW872 Cells. Main methods SW872 Cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extraCellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively. Key findings High expression of SERCA2b promoted Cell proliferation and blocked the differentiation potential of SW872 Cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes. Significance The results revealed a novel role of SERCA2b in facilitating the blockade of human Liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human Liposarcoma.
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Targeting Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase 2 by Curcumin Induces ER Stress-Associated Apoptosis for Treating Human Liposarcoma
Molecular cancer therapeutics, 2011Co-Authors: Lu Wang, Yang Sun, Yan Shen, Lingxian Wang, Ran Song, Yongqian ShuAbstract:Human Liposarcoma is the most common soft tissue sarcoma. There is no effective therapy so far except for surgery. In this study, we report for the first time that curcumin induces endoplasmic reticulum (ER) stress in human Liposarcoma Cells via interacting with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2). Curcumin dose-dependently inhibited the Cell survival of human Liposarcoma Cell line SW872 Cells, but did not affect that of human normal adipose-derived Cells. Curcumin-mediated ER stress via inhibiting the activity of SERCA2 caused increasing expressions of CHOP and its transcription target death receptor 5 (TRAIL-R2), leading to a caspase-3 and caspase-8 cascade-dependent apoptosis in SW872 Cells in vitro and in vivo . Moreover, 70% of human Liposarcoma tissues showed an elevated SERCA2 expression compared with normal adipose tissues. Curcumin dose-dependently inhibited the activity of SERCA2, and the interaction of molecular docking and colocalization in ER of curcumin with SERCA2 were further observed. These findings suggest that curcumin may serve as a potent agent for curing human Liposarcoma via targeting SERCA2. Mol Cancer Ther; 10(3); 461–71. ©2011 AACR .
Yongqian Shu - One of the best experts on this subject based on the ideXlab platform.
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high expression of sarcoplasmic endoplasmic reticulum ca2 atpase 2b blocks Cell differentiation in human Liposarcoma Cells
Life Sciences, 2014Co-Authors: Lu Wang, Yang Sun, Yang Yang, Yongqian Shu, Yan ShenAbstract:Abstract Aims We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca 2 + -ATPase 2 (SERCA2) was related to the malignant degree of different types of human Liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human Liposarcoma Cell line SW872 Cells. Main methods SW872 Cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extraCellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively. Key findings High expression of SERCA2b promoted Cell proliferation and blocked the differentiation potential of SW872 Cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes. Significance The results revealed a novel role of SERCA2b in facilitating the blockade of human Liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human Liposarcoma.
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High expression of sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase 2b blocks Cell differentiation in human Liposarcoma Cells
Life sciences, 2014Co-Authors: Lu Wang, Yang Sun, Yang Yang, Yongqian Shu, Yan ShenAbstract:Abstract Aims We have previously reported that elevated expression of sarcoplasmic/endoplasmic reticulum Ca 2 + -ATPase 2 (SERCA2) was related to the malignant degree of different types of human Liposarcoma. Here, we investigated the effects of high SERCA2b expression on proliferation and differentiation of preadipocyte-like human Liposarcoma Cell line SW872 Cells. Main methods SW872 Cells were stably transfected with human SERCA2b expressing plasmid. Adipocyte differentiation was assayed by adipogenic gene and protein expression. Cell proliferation, formation of reactive oxygen species (ROS) and phosphorylation of peroxisome proliferator activated receptor gamma (PPAR-γ) and extraCellular signal-regulated kinase (ERK) were determined by MTT assay, 2, 7-dichlorofluorescein diacetate (DCF-DA) assay and western blot analysis, respectively. Key findings High expression of SERCA2b promoted Cell proliferation and blocked the differentiation potential of SW872 Cells under both in vitro and in vivo differentiation-inducing environment. Moreover, high expression of SERCA2b induced accumulation of ROS and enhanced ERK signaling, thus leading to inactivation of PPAR-γ and down-regulation of adipocyte-specific genes. Significance The results revealed a novel role of SERCA2b in facilitating the blockade of human Liposarcoma differentiation, which helps provide a molecular target for therapeutic interventions of human Liposarcoma.
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Targeting Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase 2 by Curcumin Induces ER Stress-Associated Apoptosis for Treating Human Liposarcoma
Molecular cancer therapeutics, 2011Co-Authors: Lu Wang, Yang Sun, Yan Shen, Lingxian Wang, Ran Song, Yongqian ShuAbstract:Human Liposarcoma is the most common soft tissue sarcoma. There is no effective therapy so far except for surgery. In this study, we report for the first time that curcumin induces endoplasmic reticulum (ER) stress in human Liposarcoma Cells via interacting with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2). Curcumin dose-dependently inhibited the Cell survival of human Liposarcoma Cell line SW872 Cells, but did not affect that of human normal adipose-derived Cells. Curcumin-mediated ER stress via inhibiting the activity of SERCA2 caused increasing expressions of CHOP and its transcription target death receptor 5 (TRAIL-R2), leading to a caspase-3 and caspase-8 cascade-dependent apoptosis in SW872 Cells in vitro and in vivo . Moreover, 70% of human Liposarcoma tissues showed an elevated SERCA2 expression compared with normal adipose tissues. Curcumin dose-dependently inhibited the activity of SERCA2, and the interaction of molecular docking and colocalization in ER of curcumin with SERCA2 were further observed. These findings suggest that curcumin may serve as a potent agent for curing human Liposarcoma via targeting SERCA2. Mol Cancer Ther; 10(3); 461–71. ©2011 AACR .
Nicholas D. Socci - One of the best experts on this subject based on the ideXlab platform.
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miR-193b-Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells.
Cancer research, 2017Co-Authors: Ying Z. Mazzu, Nicholas D. Socci, Li-xuan Qin, Rajesh K. Soni, Kelly Mojica, Phaedra Agius, Zachary M. Waxman, Aleksandra Mihailovic, Ronald C. HendricksonAbstract:Well-differentiated and dedifferentiated Liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in Liposarcoma in vitro and in vivo Deep RNA sequencing on 93 WDLS, 145 DDLS, and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared with normal fat. Reintroduction of miR-193b induced apoptosis in Liposarcoma Cells and promoted adipogenesis in human adipose-derived stem Cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets, including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated reactive oxygen species signaling by targeting the antioxidant methionine sulfoxide reductase A to modulate Liposarcoma Cell survival and ASC differentiation state. Expression of miR-193b in Liposarcoma Cells was downregulated by promoter methylation, resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited Liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in Liposarcoma but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in Liposarcoma, some with immediate implications for therapeutic exploration. Cancer Res; 77(21); 5728-40. ©2017 AACR.
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ZIC1 Overexpression Is Oncogenic in Liposarcoma
Cancer Research, 2010Co-Authors: Elliott R. Brill, Mariana Lagos-quintana, Bernadette Laxa, Penelope Decarolis, Ryan M Gobble, Christina V Angeles, Cristina R Antonescu, Aimee M. Crago, Lei Zhang, Nicholas D. SocciAbstract:Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for Liposarcoma is surgical excision because Liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with Liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving Liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of Liposarcoma compared with normal fat, and in Liposarcoma Cell lines compared with adipose-derived stem Cells. Here, we show that ZIC1 contributes to the pathogenesis of Liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round Cell Liposarcoma Cell lines, but not in either adipose-derived stem Cells or in a lung cancer Cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for Liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for Liposarcoma. Cancer Res; 70(17); OF1–11. ©2010 AACR.
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ZIC1 Overexpression Is Oncogenic in Liposarcoma
Cancer research, 2010Co-Authors: Elliott R. Brill, Mariana Lagos-quintana, Bernadette Laxa, Penelope Decarolis, Ryan M Gobble, Christina V Angeles, Cristina R Antonescu, Aimee M. Crago, Lei Zhang, Nicholas D. SocciAbstract:Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for Liposarcoma is surgical excision because Liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with Liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving Liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of Liposarcoma compared with normal fat, and in Liposarcoma Cell lines compared with adipose-derived stem Cells. Here, we show that ZIC1 contributes to the pathogenesis of Liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round Cell Liposarcoma Cell lines, but not in either adipose-derived stem Cells or in a lung cancer Cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for Liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for Liposarcoma.
Aimee M. Crago - One of the best experts on this subject based on the ideXlab platform.
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abstract 4972 high throughput functional profiling of dedifferentiated Liposarcoma Cell lines
Cancer Research, 2011Co-Authors: Shantanu Banerji, Aimee M. Crago, Jordi Barretina, Abbie M Frederick, Michael Okamoto, Barbara A Weir, Glenn S Cowley, David E Root, Marc Ladanyi, S SingerAbstract:We previously profiled several adult soft-tissue sarcoma subtypes using sequencing, copy number analysis, and gene expression arrays. This high-throughput genetic profiling revealed dozens of candidate genes deserving of further functional validation. To prioritize genes, we performed a pooled shRNA screen to identify essential genes in Liposarcoma. Dedifferentiated Liposarcoma (DDLS) served as a model for this approach as multiple robust Cell lines are available. Five DDLS Cell lines (DDLS8817, LPS141, FU-DDLS-1, RDD8107, and LP6) were infected with a pool of 54,020 lentiviral shRNAs targeting ∼11,000 genes (median 5 shRNAs per gene) and passaged for 16 doublings. DNA was extracted and hairpin sequences were PCR amplified and hybridized to a custom microarray that interrogates all shRNAs in the pool. shRNAs were ranked according to their differential abundance between early and late passages. Genes corresponding to the most significantly depleted shRNAs are presumed to affect Cell proliferation and are candidate oncogenes. We compared the pattern of hairpin depletion in the DDLS Cell lines to a panel of over 60 Cell lines representing other common cancers screened with the same pooled shRNA library. The 5 DDLS Cell lines clustered into 3 distinct groups. Only one gene appeared to be essential in all 3 groups: WWTR1 (TAZ1), a master-regulator of adipocyte differentiation. Twenty-eight genes appeared essential in at least two DDLS groups including MDM2 and ZBTB2, both reported to negatively regulate the tumor suppressor gene TP53. Low-throughput in vitro experiments have confirmed that WWTR1 knockdown using two shRNA clones inhibits LPS141 proliferation by 78 and 75% after 4 days as compared to scramble (p=0.004 and 0.06 respectively). Our complementary genome-scaled functional screen has confirmed a known oncogene in DDLS and revealed additional candidate genes that appear to have a role in proliferation. Further integration of existing datasets may nominate additional genes essential for Liposarcoma pathogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4972. doi:10.1158/1538-7445.AM2011-4972
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ZIC1 Overexpression Is Oncogenic in Liposarcoma
Cancer Research, 2010Co-Authors: Elliott R. Brill, Mariana Lagos-quintana, Bernadette Laxa, Penelope Decarolis, Ryan M Gobble, Christina V Angeles, Cristina R Antonescu, Aimee M. Crago, Lei Zhang, Nicholas D. SocciAbstract:Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for Liposarcoma is surgical excision because Liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with Liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving Liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of Liposarcoma compared with normal fat, and in Liposarcoma Cell lines compared with adipose-derived stem Cells. Here, we show that ZIC1 contributes to the pathogenesis of Liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round Cell Liposarcoma Cell lines, but not in either adipose-derived stem Cells or in a lung cancer Cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for Liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for Liposarcoma. Cancer Res; 70(17); OF1–11. ©2010 AACR.
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ZIC1 Overexpression Is Oncogenic in Liposarcoma
Cancer research, 2010Co-Authors: Elliott R. Brill, Mariana Lagos-quintana, Bernadette Laxa, Penelope Decarolis, Ryan M Gobble, Christina V Angeles, Cristina R Antonescu, Aimee M. Crago, Lei Zhang, Nicholas D. SocciAbstract:Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for Liposarcoma is surgical excision because Liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with Liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving Liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of Liposarcoma compared with normal fat, and in Liposarcoma Cell lines compared with adipose-derived stem Cells. Here, we show that ZIC1 contributes to the pathogenesis of Liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round Cell Liposarcoma Cell lines, but not in either adipose-derived stem Cells or in a lung cancer Cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for Liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for Liposarcoma.