IGFBP-3 is regulated by Gli signaling in cartilage tumors.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE15118 | GEO | 2009/03/06
SECONDARY ACCESSION(S): PRJNA114869
REPOSITORIES: GEO
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Project description:Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed lesions similar to chondrosarcomas when also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and IGF signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limbs explants with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when also deficient for Igf2. IGF signaling meditated apoptosis regulates the progression to malignant chondrosarcoma. Experiment Overall Design: The CH10T1/2 cell line was stably transfected with either the R150C variant PTHR1 present in enchondromas (Hopyan, S., Gokgoz, N., Poon, R., Gensure, R. C., Yu, C., Cole, W. G., Bell, R. S., Juppner, H., Andrulis, I. L., Wunder, J. S., and Alman, B. A. (2002). A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet 30, 306-310) or a wild type PTHR1, as previously reported (Mau, E., Whetstone, H., Yu, C., Hopyan, S., Wunder, J. S., and Alman, B. A. (2007). PTHrP regulates growth plate chondrocyte differentiation and proliferation in a Gli3 dependent manner utilizing hedgehog ligand dependent and independent mechanisms. Dev Biol 305, 28-39). Cells were grown overnight in serum free media and treated with either 10â?? 7 M PTHrP (Bachem, King of Prussia, Pennsylvania, USA), or carrier alone for one hour. RNA was isolated from the cells CH10T1/2 cells expressing either the R150C variant PTHR1 or wild type PTHR1. RNA was converted to double-stranded cDNA using Superscript (Gibco-Invitrogen) with a T7-(dT)24 primer, which was then transcribed to biotinylated complementary RNA (cRNA) by incorporating biotin-CTP and biotin-UTP using Enzo BioArray High Yield RNA labeling kit (Enzo Diagnostics, New York, NY). The cRNA labeling and hybridizations were then performed according to Affymetrix GeneChip Protocol (Affymetrix Inc., Santa Clara, CA). The chips were scanned for fluorescence signal detection. Affymetrix - GeneChip® Mouse Genome 430A 2.0 Array was utilized.
2009-03-14 | E-GEOD-15118 | biostudies-arrayexpress
Project description:In obesity an increase in β-cell mass occurs to cope with the rise in insulin demand. This β -cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of β -cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the β -cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and β -cells is a novel mechanism that participates in the control of β -cell plasticity. (Endocrinology 153: 177–187, 2012)
2012-03-30 | GSE36935 | GEO
Project description:In obesity an increase in β-cell mass occurs to cope with the rise in insulin demand. This β -cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of β -cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the β -cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and β -cells is a novel mechanism that participates in the control of β -cell plasticity. (Endocrinology 153: 177–187, 2012) Adult male Wistar rats (Charles River Laboratories, Wilmington, MA), 7 wk old (weighing 225–250 g), were caged individually in a 12-h light, 12-h dark cycle in a temperature- and humidity-controlled environment. Animals were divided into two dietary sets for 30 days. One group was fed with standard chow diet (supplying 8% of calories as fat; type AO4 from Panlab, Barcelona, Spain). The second group was fed with a cafeteria diet (66% of calories as fat), as previously described (Endocrinology 146:4362–4369, 2005). Adipose tissue from the mesenteric surrounding the pancreas (pMES), was excised, weighed, cut, and rapidly frozen in liquid nitrogen for RNA isolation. Ten micrograms of total RNA from pMES adipose tissue were converted into cRNA, biotinylated, fragmented, and hybridized to GeneChip Rat Genome 230 2.0 (Affymetrix, Santa Clara, CA). Five microarrays were hybridized, three with independent samples coming from rats fed with standard chow (lean group) and two with independent samples coming from rats fed with the cafeteria diet (obese group).
2012-03-29 | E-GEOD-36935 | biostudies-arrayexpress
Project description:Despite significant progress in therapy, melanoma is still the most lethal form of skin cancer, with a rising incidence worldwide. Little is known about the impact of deregulated Hedgehog-GLI (HH-GLI) signalling pathway in the progression of this disease. Based on previous research, we hypothesized that in melanoma activation of HH-GLI signaling pathway is non- canonical due to its crosstalk with MAPK signaling pathway, which is the most deregulated pathway in melanoma. In order to investigate the link between the two pathways and to find novel GLI transcriptional targets that could be considered for potential combination therapy, we performed RNA sequencing on three melanoma cell lines with overexpressed GLI1, GLI2 and GLI3 and combined them with results of ChIP sequencing on endogenous GLI1, GLI2 and GLI3 proteins on the same cell lines. RNA-seq revealed a total of 808 DEGs for GLI1, 941 DEGs for GLI2 and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. After combining these results, 21 targets were selected for validation by qPCR. Fifteen of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq.
2023-01-01 | E-MTAB-11936 | biostudies-arrayexpress
Project description:Combination of platinum-based chemotherapy and radiation is currently the standard treatment for locally advanced lung cancer patients. However, therapeutic resistance to these therapies may arise from the presence of cancer stem cells (CSCs). To investigate the CSCs hypothesis of chemo-radiation resistance, we used microarray assay to profile CSCs-like cisplatin-resistant lung cancer cells (CDDP-R) versus its parental cells. CDDP-R cells were established by exposing H460 lung cancer cells to 3µM cisplatin for 7 days, followed by 0.8% methylcellulose selection over 14 consecutive days. We found that CDDP-R cells expressed higher levels of stem cell markers, including CD133 and ALDH. They are more resistant to cisplatin- and etoposide-induced apoptosis and to high radiation dose (20Gy). Clonogenic assays suggest that CDDP-R cells were more resistant to radiation than parental H460 cells (DER=1.21, p<0.01). Xenograft studies suggest that CDDP-R cells were more tumorigenic (p<0.001). Microarray and comprehensive protein interaction networks analyses revealed IGFBP3 as a highly ranked hub protein which plays an important role in the mechanism of cisplatin resistance. We found reduced level of IGFBP3 and enhanced IGFR-1 activation upon IGF stimulation in CDDP-R cells. The specific targeting of IGF-1R using siRNA resulted in significant sensitization of CDDP-cells (DER=1.17, p<0.05) to radiation compared with the parental H460 cells. Our findings suggest that CDDP-R cells have the characteristics of CSCs and constitute a “suitable” model to study lung CSCs. Profiling of CSCs-like H460 cells led to the identification of IGF as an important pathway for chemo- and radiotherapy resistance in lung cancer. gene expression comparison of two groups
2011-09-26 | E-GEOD-21656 | biostudies-arrayexpress
Project description:Proper Hedgehog (HH) signaling is essential for normal embryonic and postnatal development, while de-regulated HH signaling drives numerous pediatric and adult cancers. In pancreatic cancer, paracrine HH signaling from tumor cells to fibroblasts contributes to tumor progression. However, the role of HH signaling in pancreatic cancer remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of transcription factors (GLI1, GLI2, GLI3), key downstream effectors of HH signaling, remain poorly understood in pancreatic cancer. In this study we investigated the individual and combined roles of GLI1-3 in pancreatic cancer progression. Inducible, fibroblast-specific deletion of Gli2 and Gli3 in a mouse model of pancreatic cancer progression reduces collagen deposition and decreases immunosuppressive myeloid cell infiltration. Further, Gli2 and Gli3 deletion leads to an increase in T cells during PanIN stages and an increase in NK cells in implanted tumors, which in turn suppresses tumor growth. Surprisingly, combined loss of all three Glis leads to a widespread loss of acinar cells, an increase in macrophage infiltration, and an increase in tumor growth. Together, these data indicate that a baseline level of Gli is necessary to maintain proper balance of cell types in the pancreas, and the coordinated activity of GLI1-3 directs the fibroinflammatory response in pancreatic cancer.
2022-07-05 | GSE185748 | GEO
Project description:High levels of GLI (GLI1 and GLI2) mRNA and GLI luciferase reporter activity were detected in the androgen independent prostate cancer cell lines DU145 and PC-3 compared to the androgen-dependent LNCaP prostate cancer cell line. Subsequently, we observed that ectopic GLI1 promoted hormone independence in LNCaP cells (LNCaP-GLI1). We compared the gene expression profile of LNCaP-pBP (empty vector), LNCaP-GLI1, DU145, and PC-3 cells globally as well as to identify GLI1-regulated genes that may contribute to hormone independence. RNA was harvested and analysed from LNCap-pBP (control/reference sample), LNCaP-GLI1, DU145 and PC-3 cells
2011-02-13 | E-GEOD-27231 | biostudies-arrayexpress
Project description:Previously, we found low-carbohydrate diets slowed prostate cancer (PC) growth and increased survival vs. a Western diet in mice, by inhibiting the insulin/IGF-1 axis. Thus, we tested whether modifying carbohydrate quality to lower glycemic index (GI) without changing quantity results in similar benefits as with reduced quantity. Male SCID mice injected with LAPC-4 cells were single-housed and randomized when their tumors reached 200mm3 on average to a LoGI (48% carbohydrate kcal, from Hylon-VII) or HiGI Western diet (48% carbohydrate kcal, from sucrose). Body weight and tumor volume were measured weekly. Body composition was assessed 35 days after randomization. Blood glucose and serum insulin, IGF-1 and IGFBP3 were measured at study end when tumor volumes reached 800mm3. We analyzed gene expression of mice tumors by RNA-sequencing and human tumors using the Prostate Cancer Transcriptome Atlas. There were no significant differences in tumor volume (P>0.05), tumor proliferation (P=0.29), and overall survival (P=0.15) between groups. At 35 days after randomization, the LoGI group had 30% lower body fat (P=0.007) despite similar body weight (P=0.58). At sacrifice, LoGI mice had smaller livers (P<0.001) and lower glucose (P=0.15), insulin (P=0.11), IGF-1 (P=0.07) and IGF-1:IGFBP3 ratio (P=0.05), and higher IGFBP3 (P=0.09) vs. HiGI, although none of these metabolic differences reached statistical significance. We observed differential gene expression and pathway enrichment in mice tumors by diet. The most upregulated and downregulated gene in the LoGI group showed expression patterns more closely resembling expression in human benign prostate tissue vs. PC. In this single mouse xenograft model, consuming a low GI diet did not delay PC growth or survival vs. a high GI diet despite suggestions of decreased activation of the insulin/IGF-1 pathway. These data suggest that improving carbohydrate quality alone while consuming a high carbohydrate diet may not effectively slow PC growth.
2024-01-01 | GSE246780 | GEO
Project description:Combination of platinum-based chemotherapy and radiation is currently the standard treatment for locally advanced lung cancer patients. However, therapeutic resistance to these therapies may arise from the presence of cancer stem cells (CSCs). To investigate the CSCs hypothesis of chemo-radiation resistance, we used microarray assay to profile CSCs-like cisplatin-resistant lung cancer cells (CDDP-R) versus its parental cells. CDDP-R cells were established by exposing H460 lung cancer cells to 3µM cisplatin for 7 days, followed by 0.8% methylcellulose selection over 14 consecutive days. We found that CDDP-R cells expressed higher levels of stem cell markers, including CD133 and ALDH. They are more resistant to cisplatin- and etoposide-induced apoptosis and to high radiation dose (20Gy). Clonogenic assays suggest that CDDP-R cells were more resistant to radiation than parental H460 cells (DER=1.21, p<0.01). Xenograft studies suggest that CDDP-R cells were more tumorigenic (p<0.001). Microarray and comprehensive protein interaction networks analyses revealed IGFBP3 as a highly ranked hub protein which plays an important role in the mechanism of cisplatin resistance. We found reduced level of IGFBP3 and enhanced IGFR-1 activation upon IGF stimulation in CDDP-R cells. The specific targeting of IGF-1R using siRNA resulted in significant sensitization of CDDP-cells (DER=1.17, p<0.05) to radiation compared with the parental H460 cells. Our findings suggest that CDDP-R cells have the characteristics of CSCs and constitute a “suitable” model to study lung CSCs. Profiling of CSCs-like H460 cells led to the identification of IGF as an important pathway for chemo- and radiotherapy resistance in lung cancer.
2011-09-27 | GSE21656 | GEO
Project description:The tumor suppressor P53 plays critical roles in prohibiting cancer. P53 is rarely mutated and still functional in luminal types of breast cancer. According to current knowledge, wild type P53 function is tightly controlled by post-translational modification, such as ubiquitination. Several ubiquitin ligases were shown to regulate P53 ubiquitination and protein stability. Here, we report RNF187, a RING family ubiquitin ligase, facilitates breast cancer growth and inhibits apoptosis via modulating P53 signaling. RNF187 is elevated in breast cancer and correlates with breast cancer survival only in P53 wild type groups. The bio-informatics analysis shows that RNF187 negatively correlates P53 target gene expression, such as IGFBP3 and FAS in breast cancer. RNF187 depletion inhibits breast cancer growth and facilitates cell death. RNA sequencing analysis indicates that RNF187 could be an important modifier for P53 signaling. Further experiments show that RNF187 interacts with P53 and promotes P53 degradation via facilitating P53 poly-ubiquitination in breast cancer cells. Interesting, the in vitro ubiquitin assay shows that RNF187 could directly ubiquitinate P53, which is independent of MDM2. These finding reveals a novel direct P53 regulator and a potential therapeutic target for breast cancer.
2021-09-01 | GSE183008 | GEO