Promotion of Liver and Lung Tumorigenesis in DEN-Treated Cytoglobin-Deficient Mice

Thủy, Lê Thị Thanh; Morita, Takashi; Yoshida, Kayo; Wakasa, Kenichi; Iizuka, Masaaki; Ogawa, Tomohiro; Mori, Mami; Sekiya, Yumiko; Momen, Shinobu; Motoyama, Hideki; Ikeda, Kazuo; Yoshizato, Katsutoshi; Kawada, Norifumi

doi:10.1016/j.ajpath.2011.05.006

Cited by 81 publications

(63 citation statements)

References 46 publications

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“…Using a model of colitis in mice, Yassin et al (2018) observed that Cygb-deficient mice developed more severe inflammation and that TNF-α increases Cygb mRNA expression in colonic epithelial cells, which might support a role for Cygb as a cytoprotective protein during inflammation. In addition, Cygb-deficient mice show elevated TNF-α and IL-6 in tumor and non-tumor tissue of the liver and lung (Thuy et al, 2011). These findings indicate that Cygb deficiency can trigger inflammation, which may contribute to increased susceptibility to cancer development (Roh et al, 2003;Park et al, 2010;Tsukamoto et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Cytoglobin Attenuates Neuroinflammation in Lipopolysaccharide-Activated Primary Preoptic Area Cells via NF-κB Pathway Inhibition

Gomes

Sousa

Ott

et al. 2019

Front. Mol. Neurosci.

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Cytoglobin (Cygb) is a hexacoordinate protein, associated with the transport of oxygen, nitric oxide scavenging, tumor suppression and protection against oxidative stress and inflammation. This protein is expressed in brain areas including the preoptic area (POA) of the anterior hypothalamus, the region responsible for the regulation of body temperature. In this study, we show that Cygb is upregulated in the rat hypothalamus 2.5 h and 5 h after intravenous administration of lipopolysaccharide (LPS). We investigated the effect of treatment with Cygb in POA primary cultures stimulated with LPS for 4 h. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured and the results showed that Cygb reduced the concentrations of both cytokines. We further observed a decrease in immunoreactivity of the inflammatory transcription factor nuclear factor-κB (NF-κB), but not NF-IL6 and STAT3, in the nucleus of Cygb-treated POA cells. These findings suggest that Cygb attenuates the secretion of IL-6 and TNF-α in LPS-stimulated POA primary cultures via inhibition of the NF-κB signaling pathway, indicating that this protein might play an important role in the control of neuroinflammation and fever.

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Section: Discussionmentioning

confidence: 99%

Cytoglobin Attenuates Neuroinflammation in Lipopolysaccharide-Activated Primary Preoptic Area Cells via NF-κB Pathway Inhibition

Gomes

Sousa

Ott

et al. 2019

Front. Mol. Neurosci.

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“…Because past reports suggest that CYGB is involved in cellular stress response 12, 19, 20 , we tested the hypothesis that CYGB regulates cell survival in the vessel wall during vascular injury. We found that CYGB is expressed in contractile VSM cells and its abundance is decreased in de-differentiated VSM cells.…”

Section: Introductionmentioning

confidence: 99%

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling

Jourd’heuil

Reilly

et al. 2017

ATVB

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Objective The role of hemoglobin and myoglobin in the cardiovascular system is well established, yet other globins in this context are poorly characterized. Here, we examined the expression and function of cytoglobin (CYGB) during vascular injury. Approach and Results We characterized CYGB content in intact vessels and primary vascular smooth muscle (VSM) cells and used two different vascular injury models to examine the functional significance of CYGB in vivo. We found that CYGB was strongly expressed in medial arterial VSM and human veins. In vitro and in vivo studies indicated that CYGB was lost upon VSM cell de-differentiation. In the rat balloon angioplasty model, site-targeted delivery of adenovirus encoding shRNA specific for CYGB prevented its re-expression and decreased neointima formation. Similarly, four weeks after complete ligation of the left common carotid, Cygb knockout mice displayed little to no evidence of neointimal hyperplasia in contrast to their wild-type littermates. Mechanistic studies in the rat indicated that this was primarily associated with increased medial cell loss, TUNEL staining, and caspase-3 activation, all indicative of prolonged apoptosis. In vitro, CYGB could be re-expressed upon VSM stimulation with cytokines and hypoxia and loss of CYGB sensitized human and rat aortic VSM cells to apoptosis. This was reversed upon antioxidant treatment or NOS2 inhibition. Conclusions These results indicate that CYGB is expressed in vessels primarily in differentiated medial vascular smooth muscle cells where it regulates neointima formation and inhibits apoptosis after injury.

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“…These results indicated that Cygb may function not only as a tumor suppressor gene, which was supported by previous studies, but also as a prognostic factor. Previous studies have indicated that Cygb loss was associated with increased cancer cell proliferation and overexpression of IL-1, IL-6, VEGF, TNFα, and TNFb mRNAs in cancer development in the liver and lungs of mice exposed to N,N-diethylnitrosamine [14]. As we known, IL-1, IL-6, VEGF and TNFα are immunosuppressive cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Cygb loss has been reported to be associated with increased cancer cell proliferation, elevated extracellular signal–regulated kinase and Akt activation, overexpression of interleukin-6 (IL-6) [14]. Deregulated signaling through phosphatidylinositol-3 kinase (PI-3K)/Akt pathways has been implicated in the malignant transformation of glial cells [15].…”

Section: Introductionmentioning

confidence: 99%

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients

Huang

Xie

et al. 2013

BMC Cancer

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BackgroundEvidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene.MethodsWe immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors.ResultsLow expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFα or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFα and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients’ overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis.ConclusionsCygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients.

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Promotion of Liver and Lung Tumorigenesis in DEN-Treated Cytoglobin-Deficient Mice

Cited by 81 publications

References 46 publications

Cytoglobin Attenuates Neuroinflammation in Lipopolysaccharide-Activated Primary Preoptic Area Cells via NF-κB Pathway Inhibition

Cytoglobin Attenuates Neuroinflammation in Lipopolysaccharide-Activated Primary Preoptic Area Cells via NF-κB Pathway Inhibition

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients

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