scholarly journals Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

2020 ◽  
Author(s):  
Xin Li ◽  
Shengdan Nie ◽  
Ziyang Lv ◽  
Lingran Ma ◽  
Yuxi Song ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Cellular Proliferation ◽  
Prognostic Significance ◽  
Glioma Cells ◽  
Tumor Grade ◽  
Prognostic Indicator ◽  
Annexin A2 ◽  
Dependent Manner ◽  
Positive Feedback Loop

Abstract Background: Glioma, with varying malignancy grades, is the most common primary brain tumor. It is urgent to set up a reliable prediction system for the tumor grade and prognosis in glioma patients. We aimed to clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients.Methods: The role of ANXA2 and GPC1 in proliferation and their relationship were validated in glioma cells. 164 glioma samples were analyzed for association between co-expression of ANXA2 and GPC1 and patient clinicopathological features and prognosis. Results: We found that ANXA2 induced glioma cellular proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both quantitative reverse transcription-polymerase chain reaction (qRT-RCR) and immunohistochemistry revealed that ANXA2 was upregulated in glioma tissues and coincided with the overexpression of GPC1. Glioma patients with high both ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). Multivariate analyses revealed that the combination of ANXA2 and GPC1 was an independent prognostic indicator for time to recurrence and OS. Conclusions: The overexpression of ANXA2 promotes proliferation by forming a GPC1/c-Myc positive feedback loop, and ANXA2 and its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma.

scholarly journals Overexpression of Annexin A2 promotes proliferation by forming a Glypican 1/c-Myc positive feedback loop: prognostic significance in human glioma

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Xin Li ◽  
Shengdan Nie ◽  
Ziyang Lv ◽  
Lingran Ma ◽  
Yuxi Song ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Prognostic Significance ◽  
Glioma Cells ◽  
Tumor Grade ◽  
Tissue Microarrays ◽  
Annexin A2 ◽  
Dependent Manner ◽  
Positive Feedback Loop ◽  
Downstream Target

AbstractIn order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma patients.

scholarly journals A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siming Qu ◽  
Li Jin ◽  
Hanfei Huang ◽  
Jie Lin ◽  
Weiwu Gao ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Hbv Infection ◽  
Cell Counting ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Liver Carcinogenesis ◽  
Nude Mouse Model ◽  
Positive Feedback Loop

Abstract Background Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. Methods The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. Result ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo. Conclusions HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

scholarly journals Floral organ abscission is regulated by a positive feedback loop

2015 ◽  
Vol 112 (9) ◽  
pp. 2906-2911 ◽  
Author(s):  
O. Rahul Patharkar ◽  
John C. Walker
Keyword(s):  
Map Kinase ◽  
Positive Feedback ◽  
Regulatory Networks ◽  
Feedback Loop ◽  
Dynamic Range ◽  
Floral Organ ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Positive Feedback Loop ◽  
Genetic Components

Abscission is the process by which plants shed unwanted organs, either as part of a natural developmental program or in response to environmental stimuli. Studies in Arabidopsis thaliana have elucidated a number of the genetic components that regulate abscission of floral organs, including a pair of related receptor-like protein kinases, HAESA and HAESA-like 2 (HAE/HSL2) that regulate a MAP kinase cascade that is required for abscission. HAE is transcriptionally up-regulated in the floral abscission zone just before cell separation. Here, we identify AGAMOUS-like 15 (AGL15; a MADS-domain transcription factor) as a putative regulator of HAE expression. Overexpression of AGL15 results in decreased expression of HAE as well as a delayed abscission phenotype. Chromatin immunoprecipitation experiments indicate that AGL15 binds the HAE promoter in floral receptacles. AGL15 is then differentially phosphorylated through development in floral receptacles in a MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4/5-dependent manner. MAP kinase phosphorylation of AGL15 is necessary for full HAE expression, thus completing a positive feedback loop controlling HAE expression. Together, the network components in this positive feedback loop constitute an emergent property that regulates the large dynamic range of gene expression (27-fold increase in HAE) observed in flowers when the abscission program is initiated. This study helps define the mechanisms and regulatory networks involved in a receptor-mediated signaling pathway that controls floral organ abscission.

scholarly journals A Positive Feedback Loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin Signaling Regulates Temozolomide Resistance in Glioma

2020 ◽  
Author(s):  
Tie Liu ◽  
Jie Hu ◽  
Bo Han ◽  
Shishan Tan ◽  
Wenqing Jia ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Positive Feedback Loop ◽  
Protein Levels ◽  
Glioma Xenograft ◽  
Rna Immunoprecipitation

Abstract Background: Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP was found to be implicated in glioma progression. However, the effects of RMRP on TMZ resistance along with related molecular mechanisms are poor defined in glioma. Methods: RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic patterns were estimated by flow cytometry. The effects of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors were explored in vivo. The relationships among IGF2BP3, RMRP and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation and RNA pull-down assays. Results: RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3 and β-catenin promoted RMRP expression in glioma cells. Conclusion: RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP contributes the better management of cancers.

scholarly journals The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

2020 ◽  
Author(s):  
Qi Wang ◽  
Chi Zhang ◽  
Lei Zhang ◽  
Huairui Chen ◽  
Jun Qian ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Critical Role ◽  
Glioma Cells ◽  
U251 Cell ◽  
Positive Feedback Loop ◽  
Gene Therapy Approach ◽  
Hypoxic Conditions ◽  
Novel Target

Abstract BackgroundHypoxia is intimately associated with increased glycolysis in gliomas, and HIF-1α plays a critical role in this process. Here, we aim to show that RLIP76 is a novel target of HIF-1α and is involved in hypoxia-enhanced glycolysis in glioma cells. MethodsThe human glioma cell lines U87 and U251 were used to explore the interactions of RLIP76-HIF-1α and RLIP76-VHL using Western blot, a Biotin pull-down assay, Immunoprecipitation, and a Chromatin immunoprecipitation assay under hypoxia. U251 cells pretreated with hypoxia were used for tumor xenografts. ResultsRLIP76 is a novel target of HIF-1α and contributes to hypoxia-enhanced glycolysis in glioma cells. HIF-1α-induced RLIP76 can critically regulate the stability of HIF-1α by alleviating VHL-mediated HIF-1α ubiquitination under hypoxia. RLIP76 interacts with HIF-1α and VHL through an RLIP76 GAP-dependent mechanism. The GAP function of RLIP76 regulates its complex formation because of the dependence of RLIP76 GAP on interactions between RLIP76 and these proteins. RLIP76 knockdown results in decreased U251 cell growth after hypoxia pretreatment in vivo. ConclusionsThis study reveals a positive feedback loop between HIF-1α and RLIP76, suggesting that RLIP76 may undergo a complex series of GAP-dependent interactions with HIF-1α and VHL to protect HIF-1α from degradation while promoting glycolysis under hypoxic conditions. We indicate that RLIP76 is crucial for the regulation of hypoxia-enhanced glycolysis and may provide a new gene therapy approach for glioma patients.

scholarly journals ITGB1-DT Facilitates Lung Adenocarcinoma Progression via Forming a Positive Feedback Loop With ITGB1/Wnt/β-Catenin/MYC

2021 ◽  
Vol 9 ◽  
Author(s):  
Ruimin Chang ◽  
Xiaoxiong Xiao ◽  
Yao Fu ◽  
Chunfang Zhang ◽  
Xiaoyan Zhu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Cellular Proliferation ◽  
Disease Free Survival ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Positive Feedback Loop ◽  
Downstream Target

Lung adenocarcinoma (LUAD) is the main histological type of lung cancer, which is the leading cause of cancer-related deaths. Long non-coding RNAs (lncRNAs) were recently revealed to be involved in various cancers. However, the clinical relevance and potential biological roles of most lncRNAs in LUAD remain unclear. Here, we identified a prognosis-related lncRNA ITGB1-DT in LUAD. ITGB1-DT was upregulated in LUAD and high expression of ITGB1-DT was correlated with advanced clinical stages and poor overall survival and disease-free survival. Enhanced expression of ITGB1-DT facilitated LUAD cellular proliferation, migration, and invasion, and also lung metastasis in vivo. Knockdown of ITGB1-DT repressed LUAD cellular proliferation, migration, and invasion. ITGB1-DT interacted with EZH2, repressed the binding of EZH2 to ITGB1 promoter, reduced H3K27me3 levels at ITGB1 promoter region, and therefore activated ITGB1 expression. Through upregulating ITGB1, ITGB1-DT activated Wnt/β-catenin pathway and its downstream target MYC in LUAD. The expressions of ITGB1-DT, ITGB1, and MYC were positively correlated with each other in LUAD tissues. Intriguingly, ITGB1-DT was found as a transcriptional target of MYC. MYC directly transcriptionally activated ITGB1-DT expression. Thus, ITGB1-DT formed a positive feedback loop with ITGB1/Wnt/β-catenin/MYC. The oncogenic roles of ITGB1-DT were reversed by depletion of ITGB1 or inhibition of Wnt/β-catenin pathway. In summary, these findings revealed ITGB1-DT as a prognosis-related and oncogenic lncRNA in LUAD via activating the ITGB1-DT/ITGB1/Wnt/β-catenin/MYC positive feedback loop. These results implicated ITGB1-DT as a potential prognostic biomarker and therapeutic target for LUAD.

scholarly journals Diabetes-Induced Oxidative Stress in Endothelial Progenitor Cells May Be Sustained by a Positive Feedback Loop Involving High Mobility Group Box-1

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Han Wu ◽  
Ran Li ◽  
Zhong-Hai Wei ◽  
Xin-Lin Zhang ◽  
Jian-Zhou Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Culture ◽  
Positive Feedback ◽  
Feedback Loop ◽  
High Mobility ◽  
High Mobility Group ◽  
Dependent Manner ◽  
Endothelial Progenitor ◽  
Positive Feedback Loop ◽  
Culture Supernatants

Oxidative stress is considered to be a critical factor in diabetes-induced endothelial progenitor cell (EPC) dysfunction, although the underlying mechanisms are not fully understood. In this study, we investigated the role of high mobility group box-1 (HMGB-1) in diabetes-induced oxidative stress. HMGB-1 was upregulated in both serum and bone marrow-derived monocytes from diabetic mice compared with control mice. In vitro, advanced glycation end productions (AGEs) induced, expression of HMGB-1 in EPCs and in cell culture supernatants in a dose-dependent manner. However, inhibition of oxidative stress with N-acetylcysteine (NAC) partially inhibited the induction of HMGB-1 induced by AGEs. Furthermore, p66shc expression in EPCs induced by AGEs was abrogated by incubation with glycyrrhizin (Gly), while increased superoxide dismutase (SOD) activity in cell culture supernatants was observed in the Gly treated group. Thus, HMGB-1 may play an important role in diabetes-induced oxidative stress in EPCs via a positive feedback loop involving the AGE/reactive oxygen species/HMGB-1 pathway.

scholarly journals Arabidopsis vascular complexity and connectivity controls PIN-FORMED1 dynamics and lateral vein patterning during embryogenesis

Development ◽  
2021 ◽  
Author(s):  
Makoto Yanagisawa ◽  
Arthur Poitout ◽  
Marisa S. Otegui
Keyword(s):  
Plasma Membrane ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Transmembrane Protein ◽  
Vascular Development ◽  
Lateral Vein ◽  
Dependent Manner ◽  
Positive Feedback Loop ◽  
Vein Patterning ◽  
Auxin Efflux Carrier

Arabidopsis VASCULATURE COMPLEXITY AND CONNECTIVITY (VCC) is a plant-specific transmembrane protein that controls the development of veins in cotyledons. Here we show that the expression and localization of the auxin efflux carrier PIN-FORMED1 (PIN1) is altered in vcc developing cotyledons and that overexpression of PIN1-GFP partially rescues vascular defects of vcc in a dosage-dependent manner. Genetic analyses suggest that VCC and PINOID (PID), a kinase that regulates PIN1 polarity, are both required for PIN1-mediated control of vasculature development. VCC expression is upregulated by auxin, likely as part of a positive feedback loop for the progression of vascular development. VCC and PIN1 localized to the plasma membrane in pre-procambial cells but are actively redirected to vacuoles in procambial cells for degradation. In the vcc mutant, PIN1 failed to properly polarize in pre-procambial cells during the formation of basal strands and instead, it is prematurely degraded in vacuoles. VCC plays a role in localization and stability of PIN1, which is critical for the transition of pre-procambial into procambial cells involved in the formation of basal lateral strands in embryonic cotyledons.

scholarly journals Super-Enhancer-Associated TMEM44-AS1 Aggravated Glioma Progression by Forming a Positive Feedback Loop With Myc

2021 ◽  
Author(s):  
Erbao Bian ◽  
Xueran Chen ◽  
Li Cheng ◽  
Meng Cheng ◽  
Zhigang Chen ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Colony Formation ◽  
Feedback Loop ◽  
Xenograft Model ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Positive Feedback Loop ◽  
Mouse Xenograft ◽  
Super Enhancer ◽  
Mouse Xenograft Model

Abstract BackgroundLong non-coding RNAs (lncRNAs) have been considered as one type of gene expression regulator for cancer development, but it is not clear how these are regulated. This study aimed to identify a specific lncRNA that promotes the glioma progression.MethodsRNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed genes. CCK-8, transwell migration, invasion assays and a mouse xenograft model were performed to determine the functions of TMEM44-AS1. Co-IP, ChIP, Dual-luciferase reporter assays, RNA pulldown and RNA immunoprecipitation assays were performed to study the molecular mechanism of TMEM44-AS1 and the downstream target.ResultsWe identified a novel lncRNA TMEM44-AS1, which was aberrantly expressed in glioma tissues, and that increased TMEM44-AS1 expression was correlated with malignant progression and poor survival for patients with glioma. Expression of TMEM44-AS1 increased the proliferation, colony formation, migration, and invasion of glioma cells. Knockdown of TMEM44-AS1 in glioma cells reduced cell proliferation, colony formation, migration and invasion, and tumor growth in a nude mouse xenograft model. Mechanistically, TMEM44-AS1 is directly bound to the SerpinB3, and sequentially activated Myc signaling; Myc transcriptionally induced TMEM44-AS1 and directly bound to the promoter and super-enhancer of TMEM44-AS1, thus forming a positive feedback loop with TMEM44-AS. Further studies demonstrated that Myc interacts with MED1 regulates the super-enhancer of TMEM44-AS1. More importantly, a novel small-molecule Myc inhibitor, Myci975, alleviated TMEM44-AS1-promoted the growth of glioma cells. Finally, TMEM44-AS1 activated IL-6 signaling by recruiting EGR1 to the promoter of IL-6 in glioma cells. ConclusionsOur study implicates a crucial role of the TMEM44-AS1-Myc axis in glioma progression and provides a possible anti-glioma therapeutic agent.

scholarly journals A positive feedback loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin signaling regulates the progression and temozolomide resistance in glioma

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Tie Liu ◽  
Jie Hu ◽  
Bo Han ◽  
Shishan Tan ◽  
Wenqing Jia ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Positive Feedback Loop ◽  
Argonaute 2 ◽  
Protein Levels ◽  
Glioma Xenograft

AbstractDrug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.

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