Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway

Thủy, Lê Thị Thanh; Matsumoto, Yoshinari; Thuy, Tuong Thi Van; Hoang, Hai; Suoh, Maito; Urahara, Yuka; Motoyama, Hideki; Fujii, Hideki; Tamori, Akihiro; Kubo, Shoji; Takemura, Shigekazu; Morita, Takashi; Yoshizato, Katsutoshi; Kawada, Norifumi

doi:10.1016/j.ajpath.2014.12.017

Cited by 48 publications

(72 citation statements)

References 44 publications

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“…In the liver, CYGB is preferentially expressed in stellate cells and confers cytoprotection in multiple liver injury models including carbon tetrachloride administration 36 , hepatosteatosis 37 , and acetaminophen-induced hepatotoxicity 38 . Silencing of CYGB in myoblasts is sufficient to induce apoptosis and potentiated the pro-apoptotic effects of hypoxia and oxidants 12 .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Thus a possible signaling through a Cygb/PIP3 interaction would be amplified under stress conditions. In the light of the growing evidence that links Cygb and cancer [44-47], the possible relevance of Cygb in the PI3K/Akt pathway through lipid peroxidation or other mechanisms deserves further study…”

Section: Discussionmentioning

confidence: 99%

Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences

Tejero

Kapralov

Baumgartner

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Cytoglobin (Cygb) is a hexa-coordinated hemoprotein with yet to be defined physiological functions. The iron coordination and spin state of the Cygb heme group are sensitive to oxidation of two cysteine residues (Cys38/Cys83) and/or the binding of free fatty acids. However, the roles of redox vs lipid regulators of Cygb’s structural rearrangements in the context of the protein peroxidase competence are not known. Searching for physiologically relevant lipid regulators of Cygb, here we report that anionic phospholipids, particularly phosphatidylinositolphosphates, affect structural organization of the protein and modulate its iron state and peroxidase activity both conjointly and/or independently of cysteine oxidation. Thus, different anionic lipids can operate in cysteine-dependent and cysteine-independent ways as inducers of the peroxidase activity. We establish that Cygb’s peroxidase activity can be utilized for the catalysis of peroxidation of anionic phospholipids (including phosphatidylinositolphosphates) yielding mono-oxygenated molecular species. Combined with the computational simulations we propose a bipartite lipid binding model that rationalizes the modes of interactions with phospholipids, the effects on structural re-arrangements and the peroxidase activity of the hemoprotein.

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“…For example, cytoglobin ( Cygb ), expressed in HSCs, plays a protective role in controlling ROS/RNS in the inflamed liver. Deficiency of Cygb promoted HCC development in CDAA-fed Cygb −/− mouse via upregulating prooxidative genes and downregulating antioxidative genes [28]. However, ROS produced by NOX2 could inhibit proliferation of cancer stem cell-like phenotype and diminish tumor growth of HCC by PPAR- γ agonists, suggesting their protective role in the context of cancer.…”

Section: The Relationship and Interdependence Between Oxidative Stmentioning

confidence: 99%

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

Hong

Tan

et al. 2016

Oxidative Medicine and Cellular Longevity

243

179

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The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed.

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Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway

Cited by 48 publications

References 44 publications

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

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

Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

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