MCEMP1 is a potential therapeutic biomarker associated with immune infiltration in advanced gastric cancer microenvironment

Wang, Daijun; Gu, Yanmei; Huo, Chengdong; Zhao, Yang; Teng, Muzhou; Li, Yumin

doi:10.1016/j.gene.2022.146760

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…Our findings showing a role of MCEMP1 in THP-1 cell chemotaxis and migration is in line with mechanistic data of MCEMP1 function in the context of other diseases ( 31 , 32 ). In particular, it has been demonstrated that MCEMP1 may affect the proliferation, migration, and invasion of gastric cancer cells by regulating epithelial-to-mesenchymal transition ( 32 ).…”

Section: Discussionsupporting

confidence: 91%

Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner

Perrot,

Karampitsakos,

Unterman

et al. 2024

American Journal of Physiology-Cell Physiology

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Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is higher in Idiopathic Pulmonary Fibrosis (IPF) patients with increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared to controls. MCEMP1 was upregulated by TGFβ at the mRNA and protein levels in THP-1. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis-regulatory elements within the MCEMP1 promoter. We also found that MCEMP1 regulates TGFβ-mediated monocyte chemotaxis, adhesion, and migration. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression.

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Section: Discussionsupporting

confidence: 91%

Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner

Perrot,

Karampitsakos,

Unterman

et al. 2024

American Journal of Physiology-Cell Physiology

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“…Our findings showing a role of MCEMP1 in THP-1 cell chemotaxis and migration is in line with mechanistic data of MCEMP1 function in the context of other diseases (28, 29). In particular, it has been demonstrated that MCEMP1 may affect the proliferation, migration, and invasion of gastric cancer cells through regulating epithelial to mesenchymal transition (29).…”

Section: Discussionsupporting

confidence: 91%

Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is expressed in classical monocytes and alveolar macrophages in Idiopathic Pulmonary Fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ dependent manner

Perrot,

Karampitsakos,

Unterman

et al. 2023

Preprint

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BackgroundMast-Cell Expressed Membrane Protein-1 (MCEMP1) is higher in Idiopathic Pulmonary Fibrosis (IPF) patients with increased risk of death and poor outcomes. Here we seek to establish the mechanistic role of MCEMP1 in pulmonary fibrosis.MethodsMCEMP1 expression was analyzed by single-cell RNA sequencing, immunofluorescence in Peripheral Blood Mononuclear Cells (PBMC) as well as in lung tissues from IPF patients and controls. Chromatin Immunoprecipitation (ChiP) and Proximity Ligation Assay (PLA) were used to study the transcriptional regulation ofMCEMP1. Transient RNA interference and lentivirus transduction were used to knockdown and knock-in MCEMP1 in THP-1 cells to study chemotaxis, adhesion, and migration. Bulk RNA sequencing was used to identify the mechanisms by which MCEMP1 participates in monocyte function. Active RHO pull-down assay was used to validate bulk RNA sequencing results.ResultsWe identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared to controls. MCEMP1 was upregulated by TGFβ at the mRNA and protein levels in THP-1. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1cis-regulatory elements within theMCEMP1promoter. In terms of its function, we found that MCEMP1 regulates TGFβ-mediated monocyte chemotaxis, adhesion, and migration. 400 differentially expressed genes were found to increase after TGFβ stimulation of THP-1, further increased in MCEMP1 knock-in cells treated with TGFβ and decreased in MCEMP1 knockdown cells treated with TGFβ. GO annotation analysis of these genes showed enrichment for positive regulation of RHO GTPase activity and signal transduction. While TGFβ enhanced RHO GTPase activity in THP-1 cells, this effect was attenuated following MCEMP1 knockdown.ConclusionMCEMP1 is highly expressed in circulating classical monocytes and alveolar macrophages in IPF. MCEMP1 is regulated by TGFβ and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFβ in RHO activity. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression.

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“…We next extended our investigation to NOD mice (Figure 7). In this model, TYK2i treatment resulted in the downregulation of genes associated with innate immune cell proliferation (Hemgn, Mcemp1, and En2) (50)(51)(52)(53)(54). In addition, there was increased expression of genes associated with the negative regulation of the Rho signaling pathway (Arhgap4 and Arhgap45) (55,56), which has been shown to modulate immune cell viability, glucose uptake, and lactate release (Figure 7D).…”

Section: Figure 7c)mentioning

confidence: 89%

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Syed,

Ballew,

Lee

et al. 2024

Preprint

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SUMMARYTyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treatedin vitrowith IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin.In vivoadministration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GPmice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.

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MCEMP1 is a potential therapeutic biomarker associated with immune infiltration in advanced gastric cancer microenvironment

Cited by 7 publications

References 37 publications

Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner

Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner

Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is expressed in classical monocytes and alveolar macrophages in Idiopathic Pulmonary Fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ dependent manner

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

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