Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target

Li, Li; Yan, Lihan; Manoj, Shwetha; Liu, Ying; Lu, Lu

doi:10.7150/jca.19295

Cited by 47 publications

(29 citation statements)

References 49 publications

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“…In the lung, depletion of HAS2 in alveolar type II cells (ATIIC) impairs the renewal capacity of ATIIC and exacerbates lung fibrosis upon bleomycin instillation [33]. Thus, our data support an important role for an HA-rich wound ECM for proper tissue regeneration and suggest CEMIP as a potential therapeutic target in diseases in which dysregulated inflammation and HA intersect [23,29,34].…”

Section: Discussionmentioning

confidence: 54%

“…CEMIP influences the extracellular environment by participating in the catabolism of HA [28], which not only alters the strength, lubrication and hydration of ECM but also regulates adhesion, migration, proliferation and differentiation of a variety of cells [29]. We found a marked increase in CEMIP mRNA and protein expression in LH and FB of IPF patients as compared to donors.…”

Section: Discussionmentioning

confidence: 57%

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Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis

et al. 2018

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Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 57%

Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis

et al. 2018

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“…IL27RA might participate in immune regulation in CNS (Iwasaki et al, 2015;Yoshida and Hunter, 2015). CEMIP may be related to brain function and development (Yoshino et al, 2017(Yoshino et al, , 2018, MEK/ERK-induced Schwann-cell dedifferentiation (Boerboom et al, 2017), immune response in glioblastoma (Motaln et al, 2012), and WNT signaling (Li et al, 2017;Duong et al, 2018;Liang et al, 2018). It was frequently reported in colorectal cancers as well (Fink et al, 2015;Zhang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a 13-Gene Signature for Prognosis Prediction in Medulloblastoma

et al. 2020

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Background: Recent studies have identified several molecular subgroups of medulloblastoma associated with distinct clinical outcomes; however, no robust gene signature has been established for prognosis prediction. Our objective was to construct a robust gene signature-based model to predict the prognosis of patients with medulloblastoma. Methods: Expression data of medulloblastomas were acquired from the Gene Expression Omnibus (GSE85217, n = 763; GSE37418, n = 76). To identify genes associated with overall survival (OS), we performed univariate survival analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. A risk score model was constructed based on selected genes and was validated using multiple datasets. Differentially expressed genes (DEGs) between the risk groups were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein-protein interaction (PPI) analyses were performed. Network modules and hub genes were identified using Cytoscape. Furthermore, tumor microenvironment (TME) was evaluated using ESTIMATE algorithm. Tumor-infiltrating immune cells (TIICs) were inferred using CIBERSORTx. Results: A 13-gene model was constructed and validated. Patients classified as high-risk group had significantly worse OS than those as low-risk group (Training set: p < 0.0001; Validation set 1: p < 0.0001; Validation set 2: p = 0.00052). The area under the curve (AUC) of the receiver operating characteristic (ROC) analysis indicated a good performance in predicting 1-, 3-, and 5-year OS in all datasets. Multivariate analysis integrating clinical factors demonstrated that the risk score was an independent predictor for the OS (validation set 1: p = 0.001, validation set 2: p = 0.004). We then identified 265 DEGs between risk groups and PPI analysis predicted modules that were highly related to central nervous system and embryonic development. The risk score was significantly correlated with programmed deathligand 1 (PD-L1) expression (p < 0.001), as well as immune score (p = 0.035), stromal score (p = 0.010), and tumor purity (p = 0.010) in Group 4 medulloblastomas. Correlations between the 13-gene signature and the TIICs in Sonic hedgehog and Group 4 medulloblastomas were revealed.

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“…As a large protein with one G8 domain, two GG domains and four PbH1 domains, KIAA1199 has a structural basis for interactions with other molecules. Several studies have elucidated the biological function of KIAA1199 in the epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and Wnt/β-catenin signaling pathways 23 , 26 , 27 . Although initially defined as a negative regulator of inflammation 28 , ANXA1 was reported to induce MMP-1 secretion in RA FLS in response to TNF-α stimulation 29 , showing its pro-inflammatory effect.…”

Section: Discussionmentioning

confidence: 99%

Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

et al. 2021

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In inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

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Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target

Cited by 47 publications

References 49 publications

Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis

Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis

Construction and Validation of a 13-Gene Signature for Prognosis Prediction in Medulloblastoma

Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

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