SerpinB2 mediated regulation of macrophage function during enteric infection

Shea‐Donohue, Terez; Zhao, Aiping; Antalis, Toni M.

doi:10.4161/gmic.28093

Cited by 23 publications

(16 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…MRC1 is an innate pattern-recognition receptor and has functions in clearing allergens and limiting allergic inflammation ( 46 ). SerpinB2 represents an immune-regulated factor that is critical for macrophage survival ( 47 ). The increase in molecules increased with FX stimulation indicated that FX may promote macrophages toward the M2 subtype to establish an immunosuppressive environment that is beneficial for tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Zhang

Feng

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

Tumor-associated macrophages (TAMs) constitute a major component of inflammatory cells in the glioblastoma multiforme (GBM) tumor microenvironment. TAMs have been implicated in GBM angiogenesis, invasion, local tumor recurrence, and immunosuppression. Coagulation factor X (FX) is a vitamin K-dependent plasma protein that plays a role in the regulation of blood coagulation. In this study, we first found that FX was highly expressed and positively correlated with TAM density in human GBM. FX exhibited a potent chemotactic capacity to recruit macrophages and promoted macrophages toward M2 subtype polarization, accelerating GBM growth. FX bound to extracellular signal-related kinase (ERK)1/2 and inhibited p-ERK1/2 in GBM cells. FX was secreted in the tumor microenvironment and increased the phosphorylation and activation of ERK1/2 and AKT in macrophages, which may have been responsible for the M2 subtype macrophage polarization. Moreover, although the lncRNA CASC2c has been verified to function as a miR-101 competing endogenous RNA (ceRNA) to promote miR-101 target genes in GBM cells, we first confirmed that CASC2c did not function as a miR-338-3p ceRNA to promote FX expression, and that FX was a target gene of miR-338-3p. CASC2c interacted with and reciprocally repressed miR-338-3p. Both CASC2c and miR-388-3p bound to FX and commonly inhibited its expression and secretion. CASC2c repressed M2 subtype macrophage polarization. Taken together, our findings revealed a novel mechanism highlighting CASC2c and FX as potential therapeutic targets to improve GBM patients by altering the GBM microenvironment.

show abstract

Section: Discussionmentioning

confidence: 99%

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Zhang

Feng

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…SERPINB2 has been implicated in Th2 responses where it is regulated by STAT6 [10]. Other recognized transcriptional regulators include NFκB, AP-1 and C/EBPβ [11, 12].…”

Section: 0 Introductionmentioning

confidence: 99%

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Shii

Song

Maurer

et al. 2017

Molecular Immunology

View full text Add to dashboard Cite

The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream enhancer RNAs upregulated SERPINB2 and the enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the enhancer RNAs after stimulation with distinct kinetics. Knock-down of the enhancer RNAs compromised stimulus induction of promoter and enhancer chromatin changes. Conversely, over-expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by enhancer RNAs on chromatin.

show abstract

“…SerpinB2 is highly expressed in macrophages, [15][16][17] suggesting a potential role for these or other hematopoietically derived cells in the host responses to B16 melanoma and LLC observed above. To test this hypothesis, BMT was performed into N7 SerpinB2 −/− recipients and age and sex-matched WT littermate controls using either donor Figure 2B).…”

Section: The Optimal Host Response To Injected B16 Melanoma or Llc mentioning

confidence: 94%

Deficiency of plasminogen activator inhibitor‐2 results in accelerated tumor growth

Westrick

Rojkjaer

Yang

et al. 2020

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Background: Upregulation of the plasminogen activation system, including urokinase plasminogen activator (uPA), has been observed in many malignancies, suggesting that co-opting the PA system is a common method by which tumor cells accomplish extracellular matrix proteolysis. PAI-2, a serine protease inhibitor, produced from the SERPINB2 gene, inhibits circulating and extracellular matrix-tethered uPA. Decreased SERPINB2 expression has been associated with increased tumor invasiveness and metastasis for several types of cancer. PAI-2 deficiency has not been reported in humans and PAI-2-deficient (SerpinB2 −/−) mice exhibit no apparent abnormalities. Objectives: We investigated the role of PAI-2 deficiency on tumor growth and metastasis. Methods: To explore the long-term impact of PAI-2 deficiency, a cohort of SerpinB2 −/− mice were aged to >18 months, with spontaneous malignancies observed in 4/9 animals, all of apparently vascular origin. To further investigate the role of PAI-2 deficiency in malignancy, SerpinB2 −/− and wild-type control mice were injected with either B16 melanoma or Lewis lung carcinoma tumor cells, with markedly accelerated tumor growth observed in SerpinB2 −/− mice for both cell lines. To determine the relative contributions of PAI-2 from hematopoietic or nonhematopoietically derived sources, bone marrow transplants between wild-type C57BL/6J and SerpinB2 −/− mice were performed. Results and Conclusions: Our results suggest that PAI-2 deficiency increases susceptibility to spontaneous tumorigenesis in the mouse, and demonstrate that SerpinB2 expression derived from a nonhematopoietic compartment is a key host factor in the regulation of tumor growth in both the B16 melanoma and Lewis lung carcinoma models.

show abstract

SerpinB2 mediated regulation of macrophage function during enteric infection

Cited by 23 publications

References 45 publications

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Deficiency of plasminogen activator inhibitor‐2 results in accelerated tumor growth

Contact Info

Product

Resources

About