C-reactive protein promotes bone destruction in human myeloma through the CD32–p38 MAPK–Twist axis

Yang, Jing; Liu, Zhiqiang; Liu, Huan; He, Jin; Lin, Pei; Wang, Qiang; Du, Juan; Ma, Wencai; Yin, Zhimin; Davis, Eric; Orłowski, Robert Z.; Hou, Jian; Yi, Qing

doi:10.1126/scisignal.aan6282

Cited by 29 publications

(24 citation statements)

References 34 publications

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“…49 High levels of circulating LDH enhanced myeloma cell proliferation and drug resistance under stressed conditions, and correlated with poor prognosis in myeloma. [50][51][52] More importantly, HR group correlated significantly to all the aforementioned parameters of disease activity, which support the fact that MMSP5 model might have prognostic value.…”

Section: Discussionsupporting

confidence: 67%

<p>A 5-Gene Stemness Score for Rapid Determination of Risk in Multiple Myeloma</p>

Bai¹,

Chen²

2020

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Purpose: Risk stratification in patients with multiple myeloma (MM) remains a challenge. As clinicopathological characteristics have been demonstrated insufficient for exactly defining MM risk, and molecular biomarkers have become the focuses of interests. Prognostic predictions based on gene expression profiles (GEPs) have been the most accurate to this day. The purpose of our study was to construct a risk score based on stemness genes to evaluate the prognosis in MM. Materials and Methods: Bioinformatics studies by ingenuity pathway analyses in side population (SP) and non-SP (MP) cells of MM patients were performed. Firstly, co-expression network was built to confirm hub genes associated with the top five Kyoto Encyclopedia of Genes and Genomes pathways. Functional analyses of hub genes were used to confirm the biologic functions. Next, these selective genes were utilized for construction of prognostic model, and this model was validated in independent testing sets. Finally, five stemness genes (ROCK1, GSK3B, BRAF, MAPK1 and MAPK14) were used to build a MM side population 5 (MMSP5) gene model, which was demonstrated to be forcefully prognostic compared to usual clinical prognostic parameters by multivariate cox analysis. MM patients in MMSP5 low-risk group were significantly related to better prognosis than those in high-risk group in independent testing sets. Conclusion: Our study provided proof-of-concept that MMSP5 model can be adopted to evaluate recurrence risk and clinical outcome for MM. The MMSP5 model evaluated in different databases clearly indicated novel risk stratification for personalized anti-MM treatments.

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Section: Discussionsupporting

confidence: 67%

<p>A 5-Gene Stemness Score for Rapid Determination of Risk in Multiple Myeloma</p>

Bai¹,

Chen²

2020

OTT

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“…It has been reported that CRP-induced cytokine expression is also regulated by TWIST transcriptionally in myeloma cells (22). Results shown in Supplementary Figure S2 also clearly demonstrated that addition of CRP was capable of inducing TWIST via the CD32-dependent mechanism as addition of neutralizing antibodies against CD32 but not CD64 blocked CRP-induced TWIST expression by RA-FLSs.…”

Section: Crp Promotes Ra-fls To Produce Pro-inflammatory Cytokines Ansupporting

confidence: 57%

C-Reactive Protein Promotes the Activation of Fibroblast-Like Synoviocytes From Patients With Rheumatoid Arthritis

Fang

Wang

et al. 2020

Front. Immunol.

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Objective: To evaluate the biological effect and mechanisms of C-reactive protein (CRP) on the activation of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). Study design: To understand if CRP is involved in RA, expression of CRP and its receptors CD32/64 was examined in synovial tissues from RA patients and normal controls. In vitro, the potential role and mechanisms of CRP in FLS proliferation and invasion, expression of pro-inflammatory cytokines, and activation of signaling pathways were investigated in both RA-FLS and a normal human fibroblast-like synoviocyte line (HFLS). Results: Compared to normal controls, synovial tissues from 21 RA patients exhibited highly activated CRP signaling, particularly by FLSs as identified by 65% of CRP-expressing cells being CRP+vimentin+ and CD32/64+vimentin+ cells. In vitro, FLSs from RA patients, but not HFLS, showed highly reactive to CRP by largely increasing proliferative and invasive activities and expressing pro-inflammatory cytokines and chemokines, including CCL2, CXCL8, IL-6, and MMP2/9. All these changes were blocked largely by a neutralizing antibody to CD32 and, to a less extent by the anti-CD64 antibody, revealing CD32 as a primary mechanism of CRP signaling during synovial inflammation. Further studies revealed that CRP also induced synovial inflammation differentially via CD32/CD64-NF-κB or p38 pathways as blockade of CRP-CD32-NF-κB signaling inhibited CXCL8, CCL2, IL-6, whereas CRP induced RA-FLS invasiveness through CD32-p38 and MMP9 expression via the CD64-p38-dependent mechanism. Conclusions: CRP signaling is highly activated in synovial FLSs from patients with RA. CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p38 and NF-κB signaling.

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“…Recent data suggest that chronic inflammation and high CRP levels are associated with poor survival in renal cell, lung, pancreatic and breast cancer, in patients with head and neck cancer treated with radiotherapy and that CRP is associated with bone destruction in multiple myeloma. [3][4][5][6][7][8][9] CRP has been shown to supress T cell function in autoimmunity in mouse models and to suppress dendritic cell function in normals. 10 11 High CRP levels have been shown in small studies to be associated with a poor outcome with the use of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blocking antibody tremelimumab.…”

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confidence: 99%

C reactive protein impairs adaptive immunity in immune cells of patients with melanoma

Yoshida

Ichikawa

Giuroiu

et al. 2020

J Immunother Cancer

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BackgroundHigh C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma.MethodsThe effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay.ResultsIn vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients.ConclusionsThese findings suggest that high levels of CRP induce an immunosuppressivemilieuin melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer.Trial registration numberNCT01783938andNCT02983006.

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C-reactive protein promotes bone destruction in human myeloma through the CD32–p38 MAPK–Twist axis

Cited by 29 publications

References 34 publications

<p>A 5-Gene Stemness Score for Rapid Determination of Risk in Multiple Myeloma</p>

<p>A 5-Gene Stemness Score for Rapid Determination of Risk in Multiple Myeloma</p>

C-Reactive Protein Promotes the Activation of Fibroblast-Like Synoviocytes From Patients With Rheumatoid Arthritis

C reactive protein impairs adaptive immunity in immune cells of patients with melanoma

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