scholarly journals The Positive Feedback Loop of NHE1-ERK Phosphorylation Mediated by BRAFV600E Mutation Contributes to Tumorigenesis and Development of Glioblastoma

2021 ◽  
Author(s):  
Yuhui Li ◽  
Dan Li ◽  
Yankun Liu ◽  
Shuqing Wang ◽  
Mingyang Sun ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Inhibitory Effect ◽  
Occurrence Rate ◽  
Positive Feedback Loop ◽  
Downstream Target ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Activating Mutation ◽  
Proliferation And Invasion

Abstract The occurrence rate of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAFV600E) in glioblastoma multiforme (GBM) is more than 50%. Na/H exchanger 1 (NHE1), a main pH regulator affecting cell microenvironment, is hyper-expressed in GBM. However, the relationship between BRAFV600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAFV600E and an upstream factor of extracellular signal-regulated kinase (ERK). In addition, there was a positive feedback loop between NHE1-ERK phosphorylation under regulation of BRAFV600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAFV600E-mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAFV600E inhibitor and combination of them. The inhibitory effect of combination of the two inhibitors was better than each single drug both in vitro and in vivo. Combination of BRAFV600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAFV600E.

scholarly journals Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α–Positive Feedback Loop

2021 ◽  
Vol 9 ◽  
Author(s):  
Xu Liu ◽  
Kun Qiao ◽  
Kaiyuan Zhu ◽  
Xianglan Li ◽  
Chunbo Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Hypoxia Inducible Factor ◽  
The Cancer Genome Atlas ◽  
Positive Feedback Loop ◽  
Downstream Target

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

scholarly journals Positive feedback loop of regulating ERK phosphorylation in mESCs mediated by Etv5-Tet2-Fgfr2 axis

2019 ◽  
Author(s):  
Chen Fan ◽  
Kui Zhu ◽  
Yuan Liu ◽  
Mengyao Zhang ◽  
Hongxia Cao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Dynamic Equilibrium ◽  
Embryonic Stem ◽  
Feedback Loops ◽  
Fibroblast Growth ◽  
Positive Feedback Loop ◽  
Erk Phosphorylation

ABSTRACTDynamic equilibrium of extracellular signal-regulated kinase (ERK) activity is regulated elaborately by multiple feedback loops to ensure the normal self-renewal of mouse embryonic stem cells (mESCs). Previous studies on mESCs have demonstrated that the negative feedback loops are engaged to prevent the overactivated ERK phosphorylation (pERK). It is not clear whether there is any positive feedback loop involved to maintain a minimum of pERK in mESCs. Here, we found that blocking fibroblast growth factor (FGF)-ERK pathway by chemical PD0325901 downregulated the transcription of E26 transformation-specific (ETS) family transcription factor Etv5 in mESCs. In turn, knockout (KO) of Etv5 by CRISPR/Cas9 decreased pERK. Moreover, Etv5 KO enhanced the DNA methylation at promoter of fibroblast growth factor receptor 2 (Fgfr2) by downregulating DNA hydroxylase Tet2, which further decreased the expression of Fgfr2 in mESCs. Collectively, a positive feedback loop of regulating pERK was revealed in mESCs, which was mediated by Etv5-Tet2-Fgfr2 axis. Our findings provide a new paradigm for pERK regulation in mESCs and will be useful to understand the cell fate determination during early embryo development.

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 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.

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