scholarly journals Loss of ERβ expression as a common step in estrogen-dependent tumor progression

2004 ◽  
Vol 11 (3) ◽  
pp. 537-551 ◽  
Author(s):  
A Bardin ◽  
N Boulle ◽  
G Lazennec ◽  
F Vignon ◽  
P Pujol
Keyword(s):  
Tumor Progression ◽  
Target Genes ◽  
Estrogen Receptor Beta ◽  
Estrogen Signaling ◽  
Benign Tumors ◽  
Specific Gene ◽  
Normal Tissues

The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERβ expression in cancer as compared with benign tumors or normal tissues, whereas ERα expression persists. The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERα target genes by ERβ or ERβ-specific gene induction could explain that ERβ has a differential effect on proliferation as compared with ERα. ERβ may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

scholarly journals Functional characterization of human Kindlin-2 core promoter identifies a key role of SP1 in Kindlin-2 transcriptional regulation

2011 ◽  
Vol 16 (4) ◽  
Author(s):  
Ammad Khan ◽  
Takashi Shimokawa ◽  
Staffan Strömblad ◽  
Hongquan Zhang
Keyword(s):  
Transcriptional Regulation ◽  
Core Promoter ◽  
Functional Characterization ◽  
Ph Domain ◽  
Interacting Protein ◽  
Normal Tissues ◽  
Functional Aspects

AbstractKindlin-2 is a recently identified FERM and PH domain containing integrin interacting protein. Kindlin-2 is ubiquitously expressed in normal tissues. So far, much effort has been spent exploring the functional aspects of Kindlin-2. However, the transcriptional regulation of Kindlin-2 has not yet been investigated. In this study we identified and functionally characterized the promoter of the human Kindlin-2 gene. We show that the core promoter of Kindlin-2 is a 39 base pair long GC rich fragment located −122/-83 upstream of the Kindlin-2 transcription start site. Functional characterization of this core promoter region by both in silico as well as in vitro/in vivo analysis shows that the transcription factor SP1 plays an important role in regulation of Kindlin-2 expression.

scholarly journals Targeting BC200/miR218-5p Signaling Axis for Overcoming Temozolomide Resistance and Suppressing Glioma Stemness

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1859 ◽  
Author(s):  
Yu-Kai Su ◽  
Jia Wei Lin ◽  
Jing-Wen Shih ◽  
Hao-Yu Chuang ◽  
Iat-Hang Fong ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Bioinformatic Analysis ◽  
Benign Tumors ◽  
Rna Expression ◽  
Ki 67 ◽  
Normal Tissues ◽  
Significant Difference ◽  
Signaling Axis

Background: Glioblastoma (GB) is one of the most common (~30%) and lethal cancers of the central nervous system. Although new therapies are emerging, chemoresistance to treatment is one of the major challenges in cancer treatment. Brain cytoplasmic 200 (BC200) RNA, also known as BCYRN1, is a long noncoding RNA (lncRNA) that has recently emerged as one of the crucial members of the lncRNA family. BC200 atypical expression is observed in many human cancers. BC200 expression is higher in invasive cancers than in benign tumors. However, the clinical significance of BC200 and its effect on GB multiforme is still unexplored and remains unclear. Methods: BC200 expression in GB patients and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. The biological importance of BC200 was investigated in vitro and in vivo through knockdown and overexpression. Bioinformatic analysis was performed to determine miRNAs associated with BC200 RNA. Results: Our findings revealed that in GB patients, BC200 RNA expression was higher in blood and tumor tissues than in normal tissues. BC200 RNA expression have a statistically significant difference between the IDH1 and P53 status. Moreover, the BC200 RNA expression was higher than both p53, a prognostic marker of glioma, and Ki-67, a reliable indicator of tumor cell proliferation activity. Overexpression and silencing of BC200 RNA both in vitro and in vivo significantly modulated the proliferation, self-renewal, pluripotency, and temozolomide (TMZ) chemo-resistance of GB cells. It was found that the expressions of BC200 were up-regulated and that of miR-218-5p were down-regulated in GB tissues and cells. miR-218-5p inhibited the expression of BC200. Conclusions: This study is the first to show that the molecular mechanism of BC200 promotes GB oncogenicity and TMZ resistance through miR-218-5p expression modulation. Thus, the noncoding RNA BC200/miR-218-5p signaling circuit is a potential clinical biomarker or therapeutic target for GB.

scholarly journals Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

2008 ◽  
Vol 105 (46) ◽  
pp. 18012-18017 ◽  
Author(s):  
Jun Kohyama ◽  
Takuro Kojima ◽  
Eriko Takatsuka ◽  
Toru Yamashita ◽  
Jun Namiki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Epigenetic Modification ◽  
Mammalian Brain ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Neural Cells ◽  
Specific Gene Expression

Neural stem/progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes, and oligodendrocytes. It has become apparent that intracellular epigenetic modification including DNA methylation, in concert with extracellular cues such as cytokine signaling, is deeply involved in fate specification of NSCs/NPCs by defining cell-type specific gene expression. However, it is still unclear how differentiated neural cells retain their specific attributes by repressing cellular properties characteristic of other lineages. In previous work we have shown that methyl-CpG binding protein transcriptional repressors (MBDs), which are expressed predominantly in neurons in the central nervous system, inhibit astrocyte-specific gene expression by binding to highly methylated regions of their target genes. Here we report that oligodendrocytes, which do not express MBDs, can transdifferentiate into astrocytes both in vitro (cytokine stimulation) and in vivo (ischemic injury) through the activation of the JAK/STAT signaling pathway. These findings suggest that differentiation plasticity in neural cells is regulated by cell-intrinsic epigenetic mechanisms in collaboration with ambient cell-extrinsic cues.

scholarly journals PRIC295, a Nuclear Receptor Coactivator, Identified from PPAR-Interacting Cofactor Complex

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sean R. Pyper ◽  
Navin Viswakarma ◽  
Yuzhi Jia ◽  
Yi-Jun Zhu ◽  
Joseph D. Fondell ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Coactivator ◽  
Evolutionarily Conserved

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

scholarly journals miR-1272 Exerts Tumor-Suppressive Functions in Prostate Cancer via HIP1 Suppression

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 435
Author(s):  
Federica Rotundo ◽  
Denis Cominetti ◽  
Rihan El Bezawy ◽  
Stefano Percio ◽  
Valentina Doldi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Functional Characterization ◽  
Developed Countries ◽  
Membrane Turnover ◽  
Normal Tissues ◽  
Treat Prostate Cancer

The development of novel therapies or the improvement of currently used approaches to treat prostate cancer (PCa), the most frequently diagnosed male tumor in developed countries, is an urgent need. In this regard, the functional characterization of microRNAs, molecules shown to regulate a number of cancer-related pathways, is instrumental to their possible clinical exploitation. Here, we demonstrate the tumor-suppressive role of the so far uncharacterized miR-1272, which we found to be significantly down-modulated in PCa clinical specimens compared to normal tissues. Through a gain-of-function approach using miRNA mimics, we showed that miR-1272 supplementation in two PCa cell models (DU145 and 22Rv1) reverted the mesenchymal phenotype by affecting migratory and invasive properties, and reduced cell growth in vitro and in vivo in SCID mice. Additionally, by targeting HIP1 encoding the endocytic protein HIP1, miR-1272 balanced EGFR membrane turnover, thus affecting the downstream AKT/ERK pathways, and, ultimately, increasing PCa cell response to ionizing radiation. Overall, our results show that miR-1272 reconstitution can affect several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy to be pursued for PCa, with the multiple aim of reducing tumor growth, enhancing response to radiotherapy and limiting metastatic dissemination.

scholarly journals Synthetic Lethality Screening Highlights Colorectal Cancer Vulnerability to Concomitant Blockade of NEDD8 and EGFR Pathways

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3805
Author(s):  
Federica Invrea ◽  
Simona Punzi ◽  
Consalvo Petti ◽  
Rosalba Minelli ◽  
Michael D. Peoples ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Target Genes ◽  
Enzyme Inhibitor ◽  
Synthetic Lethality ◽  
Drop Out ◽  
Specific Gene ◽  
Loss Of Function ◽  
Egfr Signaling Pathway

Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness. Primary and acquired resistance limits the efficacy of available treatments, and identification of effective drug combinations is needed to further improve patients’ outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a “drop-out” loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. These results unveil possible therapeutic opportunities in specific CRC clinical settings.

scholarly journals Circ_0001955 facilitates hepatocellular carcinoma (HCC) tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Zhicheng Yao ◽  
Ruiyun Xu ◽  
Lin Yuan ◽  
Mingxing Xu ◽  
Haiyun Zhuang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Opposite Effect ◽  
Target Genes ◽  
Circular Rnas ◽  
Rna Molecules ◽  
Normal Tissues ◽  
Tumor Tissues

AbstractCircular RNAs (circRNAs) have been increasingly demonstrated to function as novel promising therapeutic RNA molecules for diverse human diseases, including cancer. Although the important role of circRNAs has been well documented in HCC, the complex mechanisms of circRNAs in HCC need to be elucidated. Here, a novel circRNA circ_0001955 was identified from three GSE datasets (GSE7852, GSE94508, and GSE97322) as a differentially expressed circRNA between HCC and normal samples. We revealed that circ_0001955, TRAF6 and MAPK11 levels were increased, while miR-516a-5p levels were decreased in HCC tumor tissues compared to adjacent normal tissues. Knockdown of circ_0001955 repressed HCC tumor growth in vitro and in vivo, while overexpression of circ_0001955 exhibited the opposite effect. Circ_0001955 was identified as a sponge for miR-145-5p and miR-516a-5p, and TRAF6 and MAPK11 were demonstrated to be two target genes of miR-516a-5p. In conclusion, circ_0001955 facilitated HCC tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11 expression.

scholarly journals A Conserved Myc Protein Domain, MBIV, Regulates DNA Binding, Apoptosis, Transformation, and G2 Arrest

2006 ◽  
Vol 26 (11) ◽  
pp. 4226-4239 ◽  
Author(s):  
Victoria H. Cowling ◽  
Sanjay Chandriani ◽  
Michael L. Whitfield ◽  
Michael D. Cole
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Binding Activity ◽  
Protein Domain ◽  
Loss Of Function ◽  
Dna Binding Activity ◽  
Induced Apoptosis

ABSTRACT The myc family of oncogenes is well conserved throughout evolution. Here we present the characterization of a domain conserved in c-, N-, and L-Myc from fish to humans, N-Myc317-337, designated Myc box IV (MBIV). A deletion of this domain leads to a defect in Myc-induced apoptosis and in some transformation assays but not in cell proliferation. Unlike other Myc mutants, MycΔMBIV is not a simple loss-of-function mutant because it is hyperactive for G2 arrest in primary cells. Microarray analysis of genes regulated by N-MycΔMBIV reveals that it is weakened for transactivation and repression but not nearly as defective as N-MycΔMBII. Although the mutated region is not part of the previously defined DNA binding domain, we find that N-MycΔMBIV has a significantly lower affinity for DNA than the wild-type protein in vitro. Furthermore, chromatin immunoprecipitation shows reduced binding of N-MycΔMBIV to some target genes in vivo, which correlates with the defect in transactivation. Thus, this conserved domain has an unexpected role in Myc DNA binding activity. These data also provide a novel separation of Myc functions linked to the modulation of DNA binding activity.

scholarly journals TRIM8 Inhibits Breast Cancer Proliferation by Regulating Estrogen Signaling

2020 ◽  
Author(s):  
Zelin Tian ◽  
Jianing Tang ◽  
Xing Liao ◽  
Qian Yang ◽  
Yumin Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Estrogen Signaling ◽  
Endocrine Treatment ◽  
Interaction Domain ◽  
Expression Levels ◽  
Protein Ubiquitination ◽  
Er Positive

Abstract Background: Breast cancer (BC) ranks first in female malignancies wordwide, 70% of which are estrogen receptor alpha (ERα) positive. Endocrine treatment, such as tamoxifen, is primary adjuvant therapy for patients with ER-positive BC, while some of them can develop acquired resistance during long-time treatment. Thus, further research on estrogen signaling is of significance to improve the prognosis of BC patients. Methods: In this study, we report that the E3 ubiquitin ligase TRIM8 acts as a novel regulator of ERα signaling. TRIM8 and ERα target genes expression levels were measured by RT-PCR, while protein expression levels were measured by western blot. CCK8 assay, clone formation, and EDU assay were used to measure cells proliferation. Wound healing assay was used to measure cells migration. Protein stability assay and protein ubiquitination analysis were used to detect ERα protein degradation. Co-immunoprecipitation assay was used to detect the interaction domain between TRIM8 and ERα. Results: TRIM8 is downregulated in BC and is associated with poor prognosis. The protein level of TRIM8 is negatively correlated with ERα. RNA-seq result revealed that estrogen signaling maybe a potential target of TRIM8. Knockdown of TRIM8 can significantly enhance BC cell proliferation and migration in vitro and in vivo. And this effect can be reversed by ERα depletion. Further mechanistic studies have shown that TRIM8 interacts with AF1 domain of ERα via its RING domain in the cytoplasm, and affects poly-ubiquitination of ERα protein. Conclusion: Our study reveals an interesting post-translational mechanism between ERα and TRIM8 in ER-positive BC, TRIM8 may be a potential therapeutic target for BC treatment.

scholarly journals LINC00473 promotes the Taxol resistance via miR-15a in colorectal cancer

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Lin Wang ◽  
Xufeng Zhang ◽  
Li Sheng ◽  
Chun Qiu ◽  
Rongcheng Luo
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Target Genes ◽  
Tumor Regression ◽  
Large Tumor ◽  
Apoptosis Pathway ◽  
Normal Tissues ◽  
Taxol Resistance

Dysregulation of long non-coding RNAs (LncRNAs) participated into the initiation and progression of different diseases via direct regulation of proteins or indirect regulation of microRNA (miRNA)-target genes. LINC00473 is a novel carcinoma-related LncRNA and up-regulated in many cancers for tumor growth and metastasis, but its role in chemotherapy resistance is unclear. We here investigated the function of LINC00473 in colorectal cancer (CRC) in vitro and in vivo. The CRC tissues (n=20) and relative normal tissues were collected and found that LINC00473 was overexpressed in CRC tissues when compared with which in normal tissues. Highly expressed LINC00473 predicted large tumor size, high TNM stage of CRC patients. Interestingly, the tumor suppressor miR-15a was down-regulated and negatively correlated with LINC00473 levels in CRC. LINC00473 harbored the binding sites for miR-15a and reduced its availability in CRC cell line HCT116. Knockdown of LINC00473 elevated the expression of miR-15a. Moreover, in the Taxol-resistant HCT116, the LINC00473 level was further increased than that in HCT116. Knockdown of LINC00473 restored the Taxol-induced cytotoxicity, inhibited the cell vitality, colony formation and induced apoptosis, impaired the ability of migration or invasion, but these effects could be abrogated by the inhibition of miR-15a. Mechanistically, the BCL-2-related anti-apoptosis pathway was activated and the multidrug-resistant (MDR) genes LRP, MDR1 were up-regulated by LINC00473. Furthermore, inhibition of LINC00473 in vivo could overcome the Taxol resistance of CRC cells, could recover the expression of tumor suppressor miR-15a and chemotherapy-induced tumor regression, indicating that LINC00473 functioned as oncogene in CRC via miR-15a.

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