scholarly journals RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth

2018 ◽  
Vol 103 (5) ◽  
pp. 1842-1849 ◽  
Author(s):  
Deborah E Ikhena ◽  
Shimeng Liu ◽  
Stacy Kujawa ◽  
Ecem Esencan ◽  
John S Coon ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cyclin D1 ◽  
Uterine Leiomyoma ◽  
Stem Cell Population ◽  
Intermediate Cell ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Gynecologic Tumor ◽  
Receptor Activator

Abstract Context Uterine leiomyomas are the most common type of gynecologic tumor in women. Objective To determine the role of the cytokine receptor activator of nuclear factor κ-Β ligand (RANKL); its receptor, receptor activator of nuclear factor κ-Β (RANK); and the RANKL/RANK pathway inhibitor RANK-Fc in leiomyoma growth. Design Messenger RNA (mRNA) or protein levels of RANKL, RANK, and proliferation markers cyclin D1 and Ki67 were assessed in various leiomyoma tissues and cell populations. Human xenograft experiments were performed to determine the effects of RANK-Fc on leiomyoma growth in vivo. Setting Research laboratory. Patients Twenty-four regularly cycling premenopausal women (age 28 to 49 years) who were not receiving hormone therapy. Interventions None. Main Outcome Measure Tumor growth in a murine xenograft model following targeting of the RANKL/RANK pathway with RANK-Fc. Results RANKL mRNA levels in leiomyoma were significantly higher than those in myometrial tissues. The highest RANK levels were found in the leiomyoma stem cell population, which is deficient in progesterone receptor (PR). Conversely, the highest RANKL levels were found in the PR-rich leiomyoma intermediate cell (LIC) population. R5020, a PR agonist, specifically increased RANKL expression in LICs. RANK-Fc blocked RANKL-induced expression of the proliferative gene cyclin D1. Treatment with RANK-Fc also significantly decreased tumor growth in vivo and diminished the expression of proliferation marker Ki67 in tumors (P < 0.01; n = 4). Conclusions Treatment with the RANKL/RANK pathway inhibitor RANK-Fc significantly decreased human leiomyoma cell proliferation and tumor growth. This suggests that the RANKL/RANK pathway could serve as a potential target for the prevention and treatment of uterine leiomyoma.

scholarly journals Estrogen Receptor-Related Receptor α Impinges on the Estrogen Axis in Bone: Potential Function in Osteoporosis

Endocrinology ◽  
2002 ◽  
Vol 143 (9) ◽  
pp. 3658-3670 ◽  
Author(s):  
Edith Bonnelye ◽  
Vanessa Kung ◽  
Catherine Laplace ◽  
Deborah L. Galson ◽  
Jane E. Aubin
Keyword(s):  
Estrogen Receptor ◽  
Functional Role ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Post Surgery ◽  
Rat Calvaria ◽  
Receptor Activator

Abstract The orphan nuclear estrogen receptor-related receptor α (ERRα) is expressed by osteoblastic cells and plays a functional role in osteoprogenitor proliferation and differentiation. To dissect further the role of ERRα in bone, we investigated the effects of estrogen (E2) on ERRα both in vitro and in vivo. Chronic treatment of fetal rat calvaria cells with E2-stimulated bone nodule formation and up-regulated ERRα mRNA expression at early (10 h and d 8) but not later times in culture, suggesting a link between ERRα and E2 during osteoprogenitor proliferation. ERRα mRNA levels were significantly lower in ovariectomized adult rat bones vs. those of sham-operated rats early (1 d and 1 wk) post surgery, but levels returned to control levels thereafter. ERRα is also expressed in osteoclasts (tartrate-resistant acid phosphatase + multinucleated cells) in vivo and in vitro (RAW 264.7 cells) and ovariectomization lowered the OPG/receptor activator of nuclear factor κB ligand expression ratio. Down-regulation of ERRα expression via antisense treatment of rat calvaria cells not only inhibited osteogenesis but also increased adipocyte colony formation and changed the OPG/receptor activator of nuclear factor κB ligand ratio. These data suggest that ERRα is regulated by estrogen in bone in which it may play a functional role at several levels (osteoblasts, adipocytes, and osteoclasts) in E2 deficiency diseases such as osteoporosis.

Repression of cyclin D1: a novel function of MYC

1994 ◽  
Vol 14 (6) ◽  
pp. 4032-4043
Author(s):  
A Philipp ◽  
A Schneider ◽  
I Väsrik ◽  
K Finke ◽  
Y Xiong ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Transcription Initiation ◽  
Core Promoter ◽  
Constitutive Expression ◽  
Mrna Levels ◽  
Amino Terminal ◽  
3T3 Fibroblasts ◽  
Tata Element

Constitutive expression of human MYC represses mRNA levels of cyclin D1 in proliferating BALB/c-3T3 fibroblasts. We expressed a series of mutant alleles of MYC and found that downregulation of cyclin D1 is distinct from previously described properties of MYC. In particular, we found that association with Max is not required for repression of cyclin D1 by MYC in vivo. Conversely, the integrity of a small amino-terminal region (amino acids 92 to 106) of MYC is critical for repression of cyclin D1 but dispensable for transformation of established RAT1A cells. Runoff transcription assays showed that repression occurs at the level of transcription initiation. We cloned the promoter of the gene for human cyclin D1 and found that it lacks a canonical TATA element. Transcription starts at an initiator element similar to that of the adenovirus major late promoter; this element can be directly bound by USF in vitro. Expression of MYC represses the cyclin D1 promoter via core promoter elements and antagonizes USF-mediated transactivation. Taken together, our data define a new pathway for gene regulation by MYC and show that the cyclin D1 gene is a target gene for repression by MYC.

scholarly journals Effect of Dose, Timing and Delivery of Tumor Necrosis Factor Alpha as an Adjuvant in Cryosurgery of ELT-3 Uterine Leiomyoma (Fibroid) Tumor

2009 ◽  
Vol 3 (2) ◽  
Author(s):  
J. Jiang ◽  
J. Bischof
Keyword(s):  
Tumor Growth ◽  
Uterine Fibroid ◽  
Tumor Size ◽  
Uterine Leiomyoma ◽  
Mode Of Delivery ◽  
Growth Delay ◽  
Tumor Growth Delay ◽  
Tnf Α ◽  
Pre Treatment

Uterine leiomyoma (fibroid or myoma) is the most common indication for hysterectomy in premenopausal women. Cryomyolysis is a uterus sparing procedure in which a myoma is frozen by a cryoprobe, thereby causing tissue necrosis upon thawing and eventual reduction in myoma size. Unfortunately, although the iceball is readily visualized (by ultrasound-US or magnetic resonance-MR), the tissue at the periphery of the iceball is not completely destroyed. One potential solution to this problem is the use of cryosurgical adjuvants that increase cryosurgical image guidance and efficacy. Previous work in our lab has shown that TNF-α (native or as the nanodrug, CYT-6091, Cytimmune Sciences, Inc.) can act synergistically with cryosurgery to destroy all prostate cancer within an iceball. Building on this work, the current study was designed to test TNF-α as an adjuvant in an in vivo model of uterine fibroid (ELT-3) in a nude mouse. The aims of this study are to characterize in vivo: 1) the destruction of the uterine fibroid over time after cryosurgery; 2) the effect of TNF-α pre-treatment on enhancement of cryosurgery; 3) the effect of TNF-α dose, pre-treatment time and mode of delivery on the above and to note any toxicities. ELT–3 rat uterine fibroid cells were grown in the hind limb of female nude mice. TNF-α at various dose (2μg and 5μg) was administered at 1, 2 and 4 hours before cryotreatment in native or CYT-6091. Native TNF-α was injected either intra-tumorally or peri-tumorally. Injecting TNF-α solution into the center of the tumor comprised the intra-tumoral approach. For peri-tumoral injection, TNF-α solution was injected at each one of eight evenly distributed points spanning the circumference of the tumor base. CYT-6091 was administered by i.v. injection only. Cryosurgery was performed with a modified 1 mm diameter cryoprobe tip (−120°C). Freezing was allowed to continue to the visible edge of the tumor. Injury was assessed by measuring tumor-growth delay. Baseline tumor size was measured on day 0; fold-changes in tumor size are reported relative to size at day 0. Toxicity was evaluated by survival rate. Groups were 4–6 animals in each group. The data suggests that pre-treatment with TNF-α before cryosurgery significantly enhances visually guided destruction of uterine leiomyoma, and that the dose, timing and mode of delivery are important variables in optimization of this combination treatment. First, it was observed that at least four hours pretreatment with TNF-α is required to obtain the synergistic effect of TNF-α and cryoinjury. Second, peri-tumoral injection of native TNF-α, was the most effective delivery method to enhance cryoinjury at low dose (2μg), however it was also the most toxic method at high dose (5μg). On the other hand, CYT-6091, although less effective than peri-tumoral injection at 2μg, was the safest delivery mode (0% lethality at 2μg; 33% at 5μg). Finally, CYT-6091 delivery at 5μg with cryosurgery resulted in a dramatic tumor growth delay compared with cryosurgery alone. Therefore, i.v. injection of CYT-6091 followed by cryosurgery allowed the highest dose of TNF-α, the least toxicity and the best overall myoma reduction. Funding: R01 CA075284, American Medical Systems, Inc. TNF-α and CYT-6091: Cytimmune Sciences, Inc.

scholarly journals Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma

2020 ◽  
Vol 22 (10) ◽  
pp. 1439-1451
Author(s):  
Wen-Bin Yang ◽  
Che-Chia Hsu ◽  
Tsung-I Hsu ◽  
Jing-Ping Liou ◽  
Kwang-Yu Chang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Target Genes ◽  
Integration Site ◽  
Recurrent Glioblastoma ◽  
Stem Cell Population ◽  
Therapeutic Resistance ◽  
Low Grade ◽  
Human Telomerase Reverse Transcriptase ◽  
Resistant Cells

Abstract Background Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemoresistance and glioblastoma recurrence. The specificity protein 1 (Sp1) transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. Methods Sp1 acetylation in temozolomide-resistant cells and stemlike tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the histone deacetylase (HDAC)/Sp1 axis on malignant growth were examined using cell proliferation–related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with chromatin immunoprecipitation sequencing and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. Results We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating B cell-specific Mo-MLV integration site 1 (BMI1) and human telomerase reverse transcriptase (hTERT), as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolyl sulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stemlike tumorspheres. Conclusion Our study uncovers a previously unknown regulatory mechanism in which the HDAC6/Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.

scholarly journals Cyclin D1 Expression and the Inhibitory Effect of Celecoxib on Ovarian Tumor Growth in Vivo

2010 ◽  
Vol 11 (10) ◽  
pp. 3999-4013 ◽  
Author(s):  
Wei Li ◽  
Hong-Ru Jiang ◽  
Xiao-Li Xu ◽  
Jie Wang ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cyclin D1 ◽  
Ovarian Tumor ◽  
Inhibitory Effect

scholarly journals NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma

2019 ◽  
Vol 22 (1) ◽  
pp. 46-57 ◽  
Author(s):  
Yifu Song ◽  
Yang Jiang ◽  
Dongxia Tao ◽  
Zixun Wang ◽  
Run Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Transcriptional Activity ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Nuclear Factor ◽  
Malignant Phenotype ◽  
Histone Deacetylase 1 ◽  
Downstream Target

Abstract Background Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown. Methods The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo. The downstream target of NFAT2 was investigated. Results High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-κB), which inhibits NF-κB–dependent transcriptional activity. Conclusion Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.

scholarly journals Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1576 ◽  
Author(s):  
Shasika Jayarathne ◽  
April Stull ◽  
Alexandra Miranda ◽  
Shane Scoggin ◽  
Kate Claycombe-Larson ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid Synthase ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Adipose Tissue Inflammation ◽  
Tart Cherry ◽  
Tissue Inflammation ◽  
Anti Inflammatory

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism’s health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1β), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

scholarly journals Overexpression of cyclin D1 in the Dami megakaryocytic cell line causes growth arrest

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 294-304 ◽  
Author(s):  
CC Wilhide ◽  
C Van Dang ◽  
J Dipersio ◽  
AA Kenedy ◽  
PF Bray
Keyword(s):  
Cyclin D1 ◽  
Cell Line ◽  
Cell Lines ◽  
Northern Blotting ◽  
Mrna Levels ◽  
Cyclin Dependent Kinases ◽  
Megakaryocyte Differentiation ◽  
Megakaryocytic Cell

The maturation of megakaryocytes in vivo requires polyploidization or repeated duplication of DNA without cytokinesis. As DNA replication and cytokinesis are tightly regulated in somatic cells by cyclins and cyclin-dependent kinases, we sought to determine the pattern of cyclin gene expression in cells that undergo megakaryocytic differentiation and polyploidization. The Dami megakaryocytic cell line differentiates and increases ploidy in response to phorbol 12-myristate 13-acetate (PMA) stimulation in vitro. We used Northern blotting to analyze mRNA levels of cyclins A, B, C, D1, and E in PMA-induced Dami cells and found that cyclin D1 mRNA levels increased dramatically (18-fold). Similar increases in cyclin D1 mRNA were obtained for other cell lines (HEL and K562) with megakaryocytic properties, but not in HeLa cells. The increase in cyclin D1 was confirmed by Western immunoblotting of PMA-treated Dami cells. This finding suggested that cyclin D1 might participate in megakaryocyte differentiation by promoting endomitosis and/or inhibiting cell division. To address these possibilities, we constructed two stable Zn+2-inducible, cyclin D1-overexpressing Dami cell lines. Cyclin D1 expression alone was not sufficient to induce polyploidy, but in conjunction with PMA-induced differentiation, polyploidization was slightly enhanced. However, unlike other cell systems, cyclin D1 overexpression caused cessation of cell growth. Although the mechanism by which cyclin D1 may affect megakaryocyte differentiation is not clear, these data demonstrate that cyclin D1 is upregulated in differentiating megakaryocytic cells and may contribute to differentiation by arresting cell proliferation.

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