Nephronectin mediates p38 <scp>MAPK</scp>‐induced cell viability via its integrin‐binding enhancer motif

Toraskar, Jimita Prashant; Magnussen, Synnøve; Chawla, Konika; Svineng, Gunbjørg; Steigedal, Tonje S.

doi:10.1002/2211-5463.12544

Cited by 12 publications

(5 citation statements)

References 41 publications

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“…More recently, we reported the involvement of the NPNT integrin-binding motifs in enhancing BC lung metastasis in mice 19 . NPNT was also found to promote anchorage independent growth and survival, providing cancer cells with a growth benefit 19,34 . These results could indicate a functional role for NPNT in metastasis.…”

Section: Discussionmentioning

confidence: 99%

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains

Magnussen

Toraskar

Wilhelm

et al. 2020

Sci Rep

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this study demonstrates a role for the extracellular matrix protein nephronectin (npnt) in promoting experimental breast cancer brain metastasis, possibly through enhanced binding to-and migration through brain endothelial cells. With the introduction of more targeted breast cancer treatments, a prolonged survival has resulted during the last decade. Consequently, an increased number of patients develop metastasis in the brain, a challenging organ to treat. We recently reported that NPNT was highly expressed in primary breast cancer and associated with unfavourable prognosis. The current study addresses our hypothesis that npnt promotes brain metastases through its integrin-binding motifs. SAGE-sequencing revealed that NPNT was significantly up-regulated in human breast cancer tissue compared to pair-matched normal breast tissue. Human brain metastatic breast cancers expressed both NPNT and its receptor, integrin α8β1. Using an open access repository; BreastMark, we found a correlation between high NPNT mRNA levels and poor prognosis for patients with the luminal B subtype. The 66cl4 mouse cell line was used for expression of wild-type and mutant NPNT, which is unable to bind α8β1. Using an in vivo model of brain metastatic colonization, 66cl4-NPNT cells showed an increased ability to form metastatic lesions compared to cells with mutant NPNT, possibly through reduced endothelial adhesion and transmigration. Abbreviations AMPK AMP-activated protein kinase BC Breast cancer EGF Epidermal growth factor EGFR Epidermal growth factor receptor EIE Glutamic acid-isoleucine-glutamic acid ER Estrogen receptor EV Empty vector FFPE Formalin fixed paraffin embedded HER2 Human epidermal growth factor receptor 2 IHC Immunohistochemistry MBEC Mouse brain endothelial cells NPNT Nephronectin

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Section: Discussionmentioning

confidence: 99%

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains

Magnussen

Toraskar

Wilhelm

et al. 2020

Sci Rep

Self Cite

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“…[36]. More recently, it was reported that Npnt is a potential prognostic marker in breast cancer and that Npnt mediates p38 mitogen-activated protein kinase (MAPK)–induced cell viability [38]. Npnt expression was suppressed by fibroblast growth factor (FGF)-2 via c-Jun N-terminal kinase (JNK) in MAPK and Phosphoinositide 3-kinase (PI3K) pathways [39].…”

Section: Silicosis and Integrinmentioning

confidence: 99%

Role of Nephronectin in Pathophysiology of Silicosis

Lee

Honda

Yamamoto

et al. 2019

IJMS

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Silicosis is a typical form of pneumoconiosis and is characterized as a type of lung fibrosis. Silica particles are captured and recognized upon by alveolar macrophages via the macrophage receptor with collagenous structure (MARCO) scavenger receptor, and thereafter the inflammasome is activated. Thereafter, various chemokines/cytokines play their roles to eventually form fibrosis. Additionally, silica particles chronically activate T helper cells which sets the background for the formation of silicosis-associated autoimmune disturbances. The occurrence and progression of lung fibrosis, the extracellular matrix-related molecules such as integrins and their ligands including fibronectin, vitronectin, laminin, and collagens, all play important roles. Here, the roles of these molecules in silicosis-related lung fibrosis are reviewed from the literature. Additionally, the measurement of serum nephronectin (Npnt), a new member of the integrin family of ligands, is discussed, together with investigations attempting to delineate the role of Npnt in silica-induced lung fibrosis. Serum Npnt was found to be higher in silicosis patients compared to healthy volunteers and seems to play a role in the progression of fibrosis with other cytokines. Therefore, serum Npnt levels may be employed as a suitable marker to monitor the progression of fibrosis in silicosis patients.

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“…Of note, multiple independent studies have implicated nephronectin in the regulation of cellular proliferation. For instance, Steigedal et al (2018) have reported that nephronectin promotes proliferation of breast cancer cells by activating the p38-MAPK signaling pathway via its integrin-binding domain ( Toraskar et al, 2018 ). Arai et al (2017) propose that nephronectin regulates proliferation of dental epithelial stem cells by activating SOX2 expression via the EGF-like repeat domains.…”

Section: Discussionmentioning

confidence: 99%

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

Hong

Kong²,

et al. 2021

Front. Cell Dev. Biol.

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Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.

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Nephronectin mediates p38 MAPK‐induced cell viability via its integrin‐binding enhancer motif

Cited by 12 publications

References 41 publications

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains

Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains

Role of Nephronectin in Pathophysiology of Silicosis

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

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