Formylpeptide receptor 1 mediates the tumorigenicity of human hepatocellular carcinoma cells

Zhang, Liang; Wang, Huanyu; Yang, Tianshu; Su, Zhifeng; Fang, Dan; Wang, Yafeng; Jia, Fang; Hou, Xiaonan; Le, Yingying; Chen, Keqiang; Wang, Ji Ming; Su, Shao Bo; Lin, Qi; Zhou, Qi

doi:10.1080/2162402x.2015.1078055

Cited by 13 publications

(13 citation statements)

References 52 publications

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“… 7 , 8 , 25 , 26 Database analyses revealed that FPR1 expression levels are upregulated in malignant glioma cells, colon cancer, lung cancer and hepatocellular carcinoma cells compared with those in normal controls. 27 – 30 According to our results, FPR1 was also overexpressed in tumor tissues from terminal-stage cervical cancer patients and from patients with poor prognosis. These observations indicated that FPR1 expression levels may serve as a diagnostic marker for cervical cancer.…”

Section: Discussionmentioning

confidence: 56%

FPR1 mediates the tumorigenicity of human cervical cancer cells

Cao¹,

Zhang²

2018

CMAR

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PurposeThe present study aimed to investigate the role of FPR1 and the downstream effectors such as NF-κB and IL-6/8 in the development of cervical cancer.Patients and methodsFPR1 protein expression was detected via immunohistochemical staining in tissue microarrays containing cervical cancer tissues from 185 patients. Following FPR1 silencing in SiHa cells using lentiviral siRNA delivery, biological characteristics and tumor formation were evaluated in vitro and in vivo, respectively. Phosphorylated NF-κB levels were detected by Western blotting, while IL-6 and IL-8 secretion were detected by ELISA in both FPR1 knockdown and control SiHa cells. Human umbilical vein endothelial cell tube formation assays were performed to evaluate the angiogenesis-promoting ability of IL-6 and IL-8 secretion in FPR1 knockdown and control SiHa cells. Neovascularization, proliferation and apoptosis markers were detected by immunohistochemical staining to analyze the tumorigenic role of FPR1.ResultsImmunohistochemistry of cervical cancer tissues from 185 patients revealed high FPR1 expression levels in patients with advanced-stage disease and/or poor prognosis. Compared with control cells, cervical cancer cells in which FPR1 was silenced exhibited inhibition of cell invasion, migration and proliferation and higher levels of apoptosis. NF-κB was inhibited in FPR1 knockdown in SiHa cells. IL-6/8 upregulation by FPR1 activation stimulated angiogenesis. FPR1 deficiency inhibited the tumorigenicity of cervical cancer cells in nude mice. FPR1, IL-6, IL-8, CD31 and Ki67 levels were all reduced, whereas cleaved caspase-3 was upregulated, in the FPR1 knockdown group compared with the levels in the control group.ConclusionHigh FPR1 expression was associated with advanced stage and poor prognosis in cervical cancer patients. FPR1 activation induced NF-κB nuclear translocation to promote cervical cancer development through the upregulation of IL-6 and IL-8 expression. Inhibiting FPR1 activity may thus have potential therapeutic value in cervical cancer patients.

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Section: Discussionmentioning

confidence: 56%

FPR1 mediates the tumorigenicity of human cervical cancer cells

Cao¹,

Zhang²

2018

CMAR

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“…The in vitro wound-healing assays were carried out as we have previously published (35). Briefly, we created a gap in the monolayer of the attached THP-1-differentiated macrophages.…”

Section: Scratch Wound-healing Modelmentioning

confidence: 99%

RELMα Licenses Macrophages for Damage-Associated Molecular Pattern Activation to Instigate Pulmonary Vascular Remodeling

Lin

Fan

Skinner

et al. 2019

The Journal of Immunology

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Pulmonary hypertension (PH) is a debilitating disease characterized by remodeling of the lung vasculature. In rodents, resistin-like molecule-a (RELMa, also known as HIMF or FIZZ1) can induce PH, but the signaling mechanisms are still unclear. In this study, we used human lung samples and a hypoxia-induced mouse model of PH. We found that the human homolog of RELMa, human (h) resistin, is upregulated in macrophage-like inflammatory cells from lung tissues of patients with idiopathic PH. Additionally, at PH onset in the mouse model, we observed RELMa-dependent lung accumulation of macrophages that expressed high levels of the key damage-associated molecular pattern (DAMP) molecule high-mobility group box 1 (HMGB1) and its receptor for advanced glycation end products (RAGE). In vitro, RELMa/hresistin-induced macrophage-specific HMGB1/RAGE expression and facilitated HMGB1 nucleus-to-cytoplasm translocation and extracellular secretion. Mechanistically, hresistin promoted HMGB1 posttranslational lysine acetylation by preserving the NAD +-dependent deacetylase sirtuin (Sirt) 1 in human macrophages. Notably, the hresistin-stimulated macrophages promoted apoptosis-resistant proliferation of human pulmonary artery smooth muscle cells in an HMGB1/RAGE-dependent manner. In the mouse model, RELMa also suppressed the Sirt1 signal in pulmonary macrophages in the early posthypoxic period. Notably, recruited macrophages in the lungs of these mice carried the RELMa binding partner Bruton tyrosine kinase (BTK). hResistin also mediated the migration of human macrophages by activating BTK in vitro. Collectively, these data reveal a vascular-immune cellular interaction in the early PH stage and suggest that targeting RELMa/DAMP-driven macrophages may offer a promising strategy to treat PH and other related vascular inflammatory diseases.

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“…For example, FPR1 expression is associated with tumor progression and survival in gastric cancer [15], and FPR1 mediates the tumorigenicity of human hepatocellular carcinoma cells [16]. High expression of FPR1 in neuroblastoma primary tumors corresponds with high-risk disease and poor patient survival [17].…”

Section: Introductionmentioning

confidence: 99%

4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists

Kirpotina

Schepetkin

Khlebnikov

et al. 2017

Biochemical Pharmacology

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Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca2+ mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells. The most active pyrroles inhibited human neutrophil Ca2+ flux, chemotaxis, and adhesion to human epithelial cells, with the most potent being compounds 14 (4-benzoyl-1-hexyl-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-2,5-dihydro-1H-pyrrol-2-one) and 17 (4-benzoyl-5-(2,5-dimethoxyphenyl)-3-hydroxy-1-(2-methoxyethyl)-2,5-dihydro-1H-pyrrol-2-one). In addition, these FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells, differentiated HL-60 cells, and human neutrophils. Most of the antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, or interleukin 8-induced Ca2+ flux in human neutrophils. Moreover, molecular modeling showed that the active pyrroles had a significantly higher degree of similarity with the FPR1 antagonist pharmacophore template as compared to inactive analogs. Thus, the 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one scaffold represents an important backbone for the development of novel FPR1 antagonists and could provide important clues for understanding the molecular structural requirements of FPR1 antagonists.

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Formylpeptide receptor 1 mediates the tumorigenicity of human hepatocellular carcinoma cells

Cited by 13 publications

References 52 publications

FPR1 mediates the tumorigenicity of human cervical cancer cells

FPR1 mediates the tumorigenicity of human cervical cancer cells

RELMα Licenses Macrophages for Damage-Associated Molecular Pattern Activation to Instigate Pulmonary Vascular Remodeling

4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists

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