scholarly journals The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Liang Liang ◽  
Wenbin Gu ◽  
Meng Li ◽  
Ran Gao ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Acquired Resistance ◽  
Regulatory Region ◽  
Leukemia Cell ◽  
Glucocorticoid Resistance ◽  
Sequencing Analysis ◽  
Resistant Cells

AbstractAcquired resistance to glucocorticoids (GCs) is an obstacle to the effective treatment of leukemia, but the molecular mechanisms of steroid insensitivity have not been fully elucidated. In this study, we established an acquired GC-resistant leukemia cell model and found a long noncoding RNA, HOTAIRM1, was overexpressed in the resistant cells by transcriptional profiling, and was higher expressed in patients with poor prognosis. The whole-genome-binding sites of HOTAIRM1 were determined by ChIRP-seq (chromatin isolation by RNA purification combined with sequencing) analysis. Further study determined that HOTAIRM1 bound to the transcriptional inhibitory region of ARHGAP18 and repressed the expression of ARHGAP18, which led to the increase of RHOA/ROCK1 signaling pathway and promoted GC resistance through antiapoptosis of leukemia cells. The inhibition of ROCK1 in GC-resistant cells could restore GCs responsiveness. In addition, HOTAIRM1 could also act as a protein sequester to prevent transcription factor AML1(acute myeloid leukemia 1) from binding to the regulatory region of ARHGAP18 by interacting with AML1. At last, we also proved AML1 could directly activate the expression of HOTAIRM1 through binding to the promoter of HOTAIRM1, which enriched the knowledge on the regulation of lncRNAs. This study revealed epigenetic causes of glucocorticoid resistance from the perspective of lncRNA, and laid a foundation for the optimization of glucocorticoid-based leukemia treatment strategy in clinic.

scholarly journals A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies

2014 ◽  
Vol 42 (15) ◽  
pp. 9588-9601 ◽  
Author(s):  
Jingnan Sun ◽  
Wei Li ◽  
Yunpeng Sun ◽  
Dehai Yu ◽  
Xue Wen ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Tyrosine Kinases ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Leukemia Cell ◽  
Paternal Allele ◽  
Type I ◽  
Gene Dysregulation ◽  
Leukemia Cell Lines ◽  
Factor Type

AbstractDysregulation of the insulin-like growth factor type I receptor (IGF1R) has been implicated in the progression and therapeutic resistance of malignancies. In acute myeloid leukemia (AML) cells, IGF1R is one of the most abundantly phosphorylated receptor tyrosine kinases, promoting cell growth through the PI3K/Akt signaling pathway. However, little is known regarding the molecular mechanisms underlying IGF1R gene dysregulation in cancer. We discovered a novel intragenic long noncoding RNA (lncRNA) within the IGF1R locus, named IRAIN, which is transcribed in an antisense direction from an intronic promoter. The IRAIN lncRNA was expressed exclusively from the paternal allele, with the maternal counterpart being silenced. Using both reverse transcription-associated trap and chromatin conformation capture assays, we demonstrate that this lncRNA interacts with chromatin DNA and is involved in the formation of an intrachromosomal enhancer/promoter loop. Knockdown of IRAIN lncRNA with shRNA abolishes this intrachromosomal interaction. In addition, IRAIN was downregulated both in leukemia cell lines and in blood obtained from high-risk AML patients. These data identify IRAIN as a new imprinted lncRNA that is involved in long-range DNA interactions.

scholarly journals Long noncoding RNA SNHG25 promotes the malignancy of endometrial cancer by sponging microRNA-497-5p and increasing FASN expression

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yuhua He ◽  
Shuifang Xu ◽  
Yi Qi ◽  
Jinfang Tian ◽  
Fengying Xu
Keyword(s):  
Endometrial Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Study Cohort ◽  
Loss Of Function ◽  
Ec Cells

Abstract Background Small nucleolar RNA host gene 25 (SNHG25), a long noncoding RNA, has been well-studied in epithelial ovarian cancer. However, the specific functions of SNHG25 in endometrial cancer (EC) have not been studied yet. In this study, we aimed to elucidate the clinical significance of SNHG25 in EC and determine the regulatory activity of SNHG25 on the tumor-associated EC phenotype. We also thoroughly explored the molecular mechanisms underlying SNHG25 function in EC. Methods Gene expression was measured using quantitative real-time polymerase chain reaction. The detailed functions of SNHG25 in EC were examined by performing loss-of-function experiments. Moreover, the regulatory mechanisms involving SNHG25, microRNA-497-5p, and fatty acid synthase (FASN) were unveiled using the luciferase reporter assay and RNA immunoprecipitation. Results We observed a high level of SNHG25 in EC using the TCGA dataset and our study cohort. Patients with a high SNHG25 level had shorter overall survival than those with a low SNHG25 level. SNHG25 deficiency resulted in tumor-repressing activities in EC cells by decreasing cell proliferation, migration, and invasion and promoting cell apoptosis. Furthermore, the function of SNHG25 depletion in impairing tumor growth in vivo was confirmed. SNHG25 sequestered miR-497-5p as a competing endogenous RNA in EC and consequently positively regulated FASN expression. Thus, the decrease in miR-497-5p or increase in FASN could neutralize the modulatory actions of SNHG25 knockdown in EC cells. Conclusions The depletion of SNHG25 impedes the oncogenicity of EC by targeting the miR-497-5p/FASN axis. The newly elucidated SNHG25/miR-497-5p/FASN pathway may be a promising target for the molecular-targeted management of EC.

scholarly journals Long noncoding RNA KCNQ1OT1 targets miRNA let-7a-5p to regulate Osteoarthritis development and progression

2021 ◽  
Author(s):  
hafiza sobia ramzan ◽  
Kashif Aziz Ahmad
Keyword(s):  
Cell Viability ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Luciferase Assay ◽  
Common Disease ◽  
Functional Roles ◽  
Non Coding Rna ◽  
Proliferation And Apoptosis ◽  
Long Non Coding Rna

Background: Osteoarthritis (OA) is a common disease of the joints among old populace until today. The treatment possibilities and roles of miRNA and long non-coding RNA (lncRNA) in therapy of OA has previously been explored. However, the functional roles of Long noncoding RNA KCNQ1OT1 and miRNA let-7a-5p on Osteoarthritis development and progression remains unclear. This study aimed at investigating the influence of KCNQ1OT1 on let-7a-5p in moderation of OA development and advancement. Materials and Methods: RT-qPCR examined expression of KCNQ1OT1and let-7a-5p in cultured human primary chondrocyte cell lines. Cell transfection overexpressed or knocked down the genes and CCK-8 assay measured cell viability in the proliferation biomarkers Ki87 and PCNA. While caspase-8 and caspase-3 activity determined rate of apoptosis. Furthermore, luciferase assay analyzed the luciferase activity and western blotting analysis determined the protein expression of KCNQ1OT1 and let-7a-5p in proliferation and apoptosis biomarkers. Results: The results demonstrated that KCNQ1OT1 is upregulated in OA-mimic cells and promotes the cell viability. KCNQ1OT1 knockdown suppresses cell viability of OA cells. Furthermore KCNQ1OT1 directly binds the 3'-UTR of let-7a-5p to negatively regulate let-7a-5p expression and OA progression. While upregulated let-7a-5p abolishes the proliferation effect of KCNQ1OT1 in OA cells. Conclusion: In summary, our study provides further insights into the underlying molecular mechanisms of KCNQ1OT1 and let-7a-5p suggesting a novel therapeutic approach to OA

Knockdown of long noncoding RNA AC245100.4 inhibits the tumorigenesis of prostate cancer cells via the STAT3/NR4A3 axis

Epigenomics ◽  
2021 ◽  
Author(s):  
Chi Liu ◽  
Ping Lin ◽  
Jiabin Zhao ◽  
Hui Xie ◽  
Rou Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Rna Sequencing ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Transcriptional Repressor ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Prostate Cancer Cells ◽  
Rna Immunoprecipitation

Aim: To explore the role and mechanism of long noncoding RNA AC245100.4 and NR4A3 in prostate cancer (PCa). Methods: RNA-sequencing analysis was used to detect the downstream genes of AC245100.4. A series of gain- and loss-of-function approaches were used to investigate the roles of AC245100.4 and NR4A3. RNA immunoprecipitation was performed to examine the interaction between AC245100.4 and STAT3. Results: AC245100.4 was significantly upregulated in PCa cells and tissues. Knockdown of AC21500.4 significantly inhibited the tumorigenesis of PCa cells. Mechanistically, AC245100.4 deregulated the transcription of NR4A3 via increasing p-STAT3, which acted as a transcriptional repressor of NR4A3. Conclusion: Knockdown of lncRNA AC245100.4 inhibits the tumorigenesis of PCa cells via the STAT3/ NR4A3 axis.

scholarly journals Long noncoding RNA LINC02582 acts downstream of miR-200c to promote radioresistance through CHK1 in breast cancer cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Baiyao Wang ◽  
Jieling Zheng ◽  
Rong Li ◽  
Yunhong Tian ◽  
Jie Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Deubiquitinating Enzyme ◽  
Downstream Target ◽  
Damage Response

Abstract Radiotherapy is essential to treat breast cancer and microRNA (miRNA) miR-200c is considered as a radiosensitizer of breast cancer. However, the molecular mechanisms by which miR-200c regulates radiosensitivity remain largely unknown. In the present study, we showed that induction of miR-200c led to widespread alteration in long noncoding RNA (lncRNA) expression in breast cancer cells. We identified lncRNA LINC02582 as a target of miR-200c. Inhibition of LINC02582 expression increased radiosensitvity, while overexpression of LINC02582 promoted radioresistance. Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance. Furthermore, we detected an inverse correlation between the expression of miR-200c vs. LINC02582 and CHK1 in breast cancer samples. These findings identified LINC02582 as a downstream target of miR-200c linking miR-200c to CHK1, in which miR-200c increases radiosensitivity by downregulation of CHK1.

scholarly journals Long noncoding RNA WEE2-AS1 plays an oncogenic role in glioblastoma by functioning as a molecular sponge for microRNA-520f-3p

2020 ◽  
Author(s):  
Hengzhou Lin ◽  
Dahui Zuo ◽  
Jiabin He ◽  
Tao Ji ◽  
Jianzhong Wang ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Tumor Diameter ◽  
Polymerase Chain ◽  
Specificity Protein

The long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) plays anoncogenic role in hepatocellular carcinoma and triple negative breast cancerprogression. In this study, we investigated the expression and roles of WEE2-AS1 inglioblastoma (GBM). Furthermore, the molecular mechanisms behind the oncogenicactions of WEE2-AS1 in GBM cells were explored in detail. WEE2-AS1 expressionwas detected using quantitative real-time polymerase chain reaction. The roles ofWEE2-AS1 in GBM cells were evaluated by the Cell Counting Kit-8 assay, flowcytometric analysis, and Transwell cell migration and invasion assays, and tumorxenograft experiments. WEE2-AS1 expression was evidently enhanced in GBM tissuesand cell lines compared with their normal counterparts. An increased level of WEE2-AS1 was correlated with the average tumor diameter, Karnofsky Performance Scalescore, and shorter overall survival among GBM patients. Functionally, depleted WEE2-AS1 attenuated GBM cell proliferation, migration, and invasion in vitro, promoted cellapoptosis, and impaired tumor growth in vivo. Mechanistically, WEE2-AS1 functionedas a molecular sponge for microRNA-520f-3p (miR-520f-3p) and consequentlyincreased specificity protein 1 (SP1) expression in GBM cells. A series of recoveryexperiments revealed that the inhibition of miR-520f-3p and upregulation of SP1 couldpartially abrogate the influences of WEE2-AS1 downregulation on GBM cells. Inconclusion, WEE2-AS1 can adsorb miR-520f-3p to increase endogenous SP1expression, thereby facilitating the malignancy of GBM. Therefore, targeting theWEE2-AS1-miR-520f-3p-SP1 pathway might be a promising therapy for themanagement of GBM in the future.

scholarly journals Long noncoding RNA-MEG3 contributes to myocardial ischemia–reperfusion injury through suppression of miR-7-5p expression

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Liyuan Zou ◽  
Xiaokun Ma ◽  
Shuo Lin ◽  
Bingyuan Wu ◽  
Yang Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter

Abstract Long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) plays an important role in protection of ischemia–reperfusion (I/R) injury in brain and liver. However, role of MEG3 in myocardial I/R injury remains unclear. Here, the role of MEG3 in protection of myocardial I/R injury and its association with microRNA-7-5p (miR-7-5p) was investigated using rat cardiac I/R model and myocardial I/R cell model. Our results showed that MEG3 was significantly up-regulated and miR-7-5p was significantly down-regulated after I/R. Following I/R, the levels of intact PARP and intact caspase-3 were reduced, while the cleaved fragments of PARP and caspase-3 were increased. TUNEL assay showed an increase in cardiomyocyte apoptosis after I/R. The levels of I/R-induced creatine kinase (CK) and lactate dehydrogenase (LDH) were inhibited by knockdown of MEG3 (siMEG3). SiMEG3 increased cell proliferation and inhibited cell apoptosis after I/R. In contrast, overexpression of MEG3 increased the I/R-induced CK and LDH activities and cell apoptosis and decreased cell proliferation. The dual-luciferase reporter system showed a direct binding of MEG3 to miR-7-5p. The level of miR-7-5p was negatively associated with the change in levels of MEG3 in H9c2 cells. The levels of intact RARP1 and caspase-3 were significantly increased by knockdown of MEG3. Co-transfection of miR-7-5p inhibitor with siMEG3 activates CK and LDH, significantly decreased cell proliferation, increased cell apoptosis, and decreased intact poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3. In summary, down-regulation of MEG3 protects myocardial cells against I/R-induced apoptosis through miR-7-5p/PARP1 pathway, which might provide a new therapeutic target for treatment of myocardial I/R injury.

scholarly journals Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome

Stroke ◽  
2021 ◽  
Author(s):  
Suresh L. Mehta ◽  
Anil K. Chokkalla ◽  
TaeHee Kim ◽  
Saivenkateshkomal Bathula ◽  
Bharath Chelluboina ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Rna Sequencing ◽  
Brain Damage ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Focal Ischemia ◽  
Developmental Expression ◽  
Lesion Volume ◽  
Sequencing Analysis ◽  
Ischemic Brain

Background and Purpose: Stroke induces the expression of several long noncoding RNAs in the brain. However, their functional significance in poststroke outcome is poorly understood. We recently observed that a brain-specific long noncoding RNA called Fos downstream transcript (FosDT) is induced rapidly in the rodent brain following focal ischemia. Using FosDT knockout rats, we presently evaluated the role of FosDT in poststroke brain damage. Methods: FosDT knockout rats were generated using CRISPR-Cas9 genome editing on a Sprague-Dawley background. Male and female FosDT −/− and FosDT +/+ cohorts were subjected to transient middle cerebral artery occlusion. Postischemic sensorimotor deficits were evaluated between days 1 and 7 and lesion volume on day 7 of reperfusion. The developmental expression profile of FosDT was determined with real-time polymerase chain reaction and mechanistic implications of FosDT in the ischemic brain were conducted with RNA-sequencing analysis and immunostaining of pathological markers. Results: FosDT expression is developmentally regulated, with the adult cerebral cortex showing significantly higher FosDT expression than neonates. FosDT −/− rats did not show any anomalies in growth and development, fertility, brain cytoarchitecture, and cerebral vasculature. However, when subjected to transient focal ischemia, FosDT −/− rats of both sexes showed enhanced sensorimotor recovery and reduced brain damage. RNA-sequencing analysis showed that improved poststroke functional outcome in FosDT −/− rats is partially associated with curtailed induction of inflammatory genes, reduced apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusions: Our study shows that FosDT is developmentally dispensable, mechanistically important, and a functionally promising target to reduce ischemic brain damage and facilitate neurological recovery.

A Review on The Role of VEGF in Tamoxifen Resistance

2019 ◽  
Vol 18 (14) ◽  
pp. 2006-2009 ◽  
Author(s):  
Sepideh Mansouri ◽  
Nikta Feizi ◽  
Ali Mahdi ◽  
Keivan Majidzadeh-A ◽  
Leila Farahmand
Keyword(s):  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Tamoxifen Resistance ◽  
Tumor Proliferation ◽  
Vegf Receptors ◽  
Over Expression ◽  
Tamoxifen Resistant ◽  
Resistant Cells

Background: Certain molecular deviations can lead to the development of breast cancer. For instance, estrogen and estrogen receptors play a significant role in inducing tumor proliferation. However, the efficacy of endocrine therapy through the administration of anti-estrogen drugs, such as Tamoxifen, is challenged by acquired resistance. Methods: Relevant articles were retrieved from Medline and google scholar. All were screened to select the ones discussing the molecular mechanisms of angiogenesis and Tamoxifen resistance. The molecular interactions contributing in the resistant network were studied from the eligible articles. Results: Tamoxifen resistance occurs as a consequence of over-activated signal transduction pathways such as RTK s dependent cascades. It has been shown that microvessel count was greater in Tamoxifen resistant tissues than in responsive ones. Conclusion: In this review, the interaction between estrogen, Tamoxifen, VEGF, and VEGF receptors (VEGFRs) in Tamoxifen resistant cells has been discussed. VEGF and estrogen-independent growth cascades, especially MAPK have a positive feedback loop in Tamoxifen resistant cells. It has been proposed that over-activated pathways in Tamoxifen resistant cells induce pin1 mediated VEGF over-expression, which in turn result in enhanced activation of MAPK.

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