HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

Wang, Lin; Lu, Yifan; Wang, Chaoshan; Xie, Yu; Zhao, Yanqiu; Qian, Ying-Chen; Liu, Weitao; Wang, Min; Jiang, Bing‐Hua

doi:10.3389/fonc.2020.01019

Cited by 14 publications

(5 citation statements)

References 42 publications

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“…EGFR activation promotes dimer PKM2 expression and nuclear translocation to activate HIF-1α, contributing to abnormal glycolysis and tumor cell proliferation ( Yang et al, 2011 ; Yang et al, 2018 ; Wang et al, 2020 ). EGFR activation promotes HIF-1α activation and ECM accumulation in mesangial cells in response to high glucose, which finally resulted in matrix upregulation and glomerular fibrosis ( Uttarwar et al, 2011 ; Li et al, 2015 ), but the exact regulatory mechanism of ARAP1 on EGFR activation and PKM2/HIF-1ɑ pathway in mesangial cells has not been reported.…”

Section: Resultsmentioning

confidence: 99%

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

Ma²,

Wang³

et al. 2023

Front. Pharmacol.

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Objectives: Dimeric pyruvate kinase (PK) M2 (PKM2) plays an important role in promoting the accumulation of hypoxia-inducible factor (HIF)-1α, mediating aberrant glycolysis and inducing fibrosis in diabetic kidney disease (DKD). The aim of this work was to dissect a novel regulatory mechanism of Yin and Yang 1 (YY1) on lncRNA-ARAP1-AS2/ARAP1 to regulate EGFR/PKM2/HIF-1α pathway and glycolysis in DKD.Materials and methods: We used adeno-associated virus (AAV)-ARAP1 shRNA to knocked down ARAP1 in diabetic mice and overexpressed or knocked down YY1, ARAP1-AS2 and ARAP1 expression in human glomerular mesangial cells. Gene levels were assessed by Western blotting, RT-qPCR, immunofluorescence staining and immunohistochemistry. Molecular interactions were determined by RNA pull-down, co-immunoprecipitation, ubiquitination assay and dual-luciferase reporter analysis.Results: YY1, ARAP1-AS2, ARAP1, HIF-1α, glycolysis and fibrosis genes expressions were upregulated and ARAP1 knockdown could inhibit dimeric PKM2 expression and partly restore tetrameric PKM2 formation, while downregulate HIF-1α accumulation and aberrant glycolysis and fibrosis in in-vivo and in-vitro DKD models. ARAP1 knockdown attenuates renal injury and renal dysfunction in diabetic mice. ARAP1 maintains EGFR overactivation in-vivo and in-vitro DKD models. Mechanistically, YY1 transcriptionally upregulates ARAP1-AS2 and indirectly regulates ARAP1 and subsequently promotes EGFR activation, HIF-1α accumulation and aberrant glycolysis and fibrosis.Conclusion: Our results first highlight the role of the novel regulatory mechanism of YY1 on ARAP1-AS2 and ARAP1 in promoting aberrant glycolysis and fibrosis by EGFR/PKM2/HIF-1α pathway in DKD and provide potential therapeutic strategies for DKD treatments.

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Section: Resultsmentioning

confidence: 99%

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

Ma²,

Wang³

et al. 2023

Front. Pharmacol.

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“…Being a potent activator of the mitogenic MAPK signaling, HB-EGF has been studied primarily in cancers as an oncogenic target, for its role in activating cell proliferation and anchorage-independent growth through autocrine signaling ( Ray et al, 2014 ; Hsieh et al, 2017 ). HB-EGF autocrine signaling is associated with breast cancer intravasation and metastasis in macrophage independent fashion, and owing to its activity on MAPK signaling, is a potent mitogen in many cancers, including lung ( Yotsumoto et al, 2017 ; Wang et al, 2020 ), pancreatic ( Ray et al, 2014 ), and breast tumors ( Sethuraman et al, 2018 ). HB-EGF is frequently referred to as an “immediate early gene” owing to its rapid transcription in response to cytoprotective or oncogenic stimuli, including ischemia reperfusion in the heart ( Xia et al, 2003 ), and in tumorogenesis ( Mccarthy et al, 1995 ).…”

Section: Discussionmentioning

confidence: 99%

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

Afzal

Du²,

Novin³

et al. 2022

Front. Cell Dev. Biol.

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Multiple parallels exist between placentation and cancer dissemination at molecular, cellular, and anatomical levels, presenting placentation as a unique model to mechanistically understand the onset of cancer metastasis. In humans, interaction of placenta and the endometrium results eventually in deep invasion of placental extravillous trophoblasts (EVTs) into the maternal stroma, a process similar to stromal trespass by disseminating carcinoma cells. In anticipation of implantation, endometrial fibroblasts (ESFs) undergo a process called decidualization during the secretory phase of the menstrual cycle. Decidualization, among other substantial changes associated with ESF differentiation, also involves a component of fibroblast activation, and myofibroblast transformation. Here, using traction force microscopy, we show that increased cellular contractility in decidualized ESFs is reversed after interaction with EVTs. We also report here the large changes in energetic state of ESFs upon decidualization, showing increased oxidative phosphorylation, mitochondrial competency and ATP generation, as well as enhanced aerobic glycolysis, presenting mechanical contractility and energetic state as new functional hallmarks for decidualization. These energetic changes accompanying the marked increase in contractile force generation in decidualization were reduced in the presence of EVTs. We also show that increase in decidual contractility and mechanical resistance to invasion is achieved by SRF-MRTF transcriptional activation, achieved via increased phosphorylation of fibroblast-specific myosin light chain 9 (MYL9). EVT induced paracrine secretion of Heparin Binding Epidermal Growth Factor (HBEGF), a potent MAPK activator, which shifts the balance of SRF association away from MRTF based transcription, reducing decidual ESF contractility and mechanical resistance to placental invasion. Our results identify a new axis of intercellular communication in the placental bed modulating stromal force generation and resistance to invasion with concurrent downregulation of cellular energetics. These findings have important implications for implantation related disorders, as well as stromal control of cancer dissemination.

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“…The soluble form (sHB-EGF) is a potent mitogen and chemoattractive to a wide variety of cells, including vascular smooth muscle cells, fibroblasts and keratinocytes. HB-EGF has been implicated in different pathological processes, such as cardiac hypertrophy 48 , 49 , smooth muscle cell hyperplasia and atherosclerotic plaque formation 50 – 52 , oncogenic transformation 53 , 54 and even hypertension and pulmonary fibrosis 55 – 57 .…”

Section: Discussionmentioning

confidence: 99%

Serum biomarkers associated with SARS-CoV-2 severity

Batista

Puga

Silva

et al. 2022

Sci Rep

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Immunity with SARS-CoV-2 infection during the acute phase is not sufficiently well understood to differentiate mild from severe cases and identify prognostic markers. We evaluated the immune response profile using a total of 71 biomarkers in sera from patients with SARS-CoV-2 infection, confirmed by RT-PCR and controls. We correlated biological marker levels with negative control (C) asymptomatic (A), nonhospitalized (mild cases-M), and hospitalized (severe cases-S) groups. Among angiogenesis markers, we identified biomarkers that were more frequently elevated in severe cases when compared to the other groups (C, A, and M). Among cardiovascular diseases, there were biomarkers with differences between the groups, with D-dimer, GDF-15, and sICAM-1 higher in the S group. The levels of the biomarkers Myoglobin and P-Selectin were lower among patients in group M compared to those in groups S and A. Important differences in cytokines and chemokines according to the clinical course were identified. Severe cases presented altered levels when compared to group C. This study helps to characterize biological markers related to angiogenesis, growth factors, heart disease, and cytokine/chemokine production in individuals infected with SARS-CoV-2, offering prognostic signatures and a basis for understanding the biological factors in disease severity.

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HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth

Cited by 14 publications

References 42 publications

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/HIF-1α pathway

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

Serum biomarkers associated with SARS-CoV-2 severity

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