Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis

Li, Guanghua; Zhao, Wang; Ye, Jinning; Zhang, Xinhua; Wu, Hui; Peng, Jianjun; Wu, Song; Chen, Chuangqi; Cai, Shirong; He, Yulong; Xu, Jianbo

doi:10.1158/0008-5472.can-14-0968

Cited by 59 publications

(56 citation statements)

References 48 publications

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“…Gene chip analysis reveals that AEG-1 overexpression leads to up-regulation of several NF-κB downstream genes, including IL-6 [9]. Consistent with the findings of previous research [9], another study demonstrates that AEG-1 knockdown could lead to the inactivation of NF-κB and down-regulation of MMP-9 [32]. Consistent with previous study [14], we showed that AEG-1 was required for NF-κB p65 activation in macrophages.…”

Section: Discussionsupporting

confidence: 64%

Elevated AEG-1 expression in macrophages promotes hypopharyngeal cancer invasion through the STAT3-MMP-9 signaling pathway

Liu

Zou

et al. 2016

Oncotarget

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Macrophages play a critical role in tumor invasion and metastasis, which remain major causes of mortality in patients with hypopharyngeal cancer. Here we investigate the effect of an oncogene, AEG-1 expressed in macrophages on the invasion of hypopharyngeal cancer cells. AEG-1 is more highly expressed in macrophages of human hypopharyngeal cancer samples compared with adjacent non-tumor controls. Using matrigel invasion assay system, THP-1-derived macrophages with forced AEG-1 overexpression enhance FaDu cell invasion whereas macrophages with AEG-1 silence inhibit. Matrix metalloproteinase 9 (MMP-9), which is important in tumor invasion and metastasis through degrading extracellular matrix, is up-reulated by AEG-1 partly through NF-κB p65 in macrophages. Intriguingly, macrophage AEG-1 also induces MMP-9 up-regulated expression in FaDu cells. Furthermore, macrophage AEG-1 activates signal transducer and activator of transcription 3 (STAT3) in FaDu cells, which is responsible for macrophage AEG-1-induced an increase in MMP-9 expression and invasion of FaDu cells. This is the first to demonstrate that macrophage AEG-1 promotes tumor invasion through up-regulation of MMP-9 in both macrophages and cancer cells. Thus, the results provide evidences that macrophage AEG-1 contributes to promotion of tumor invasion, and represents as a potential target in hypopharyngeal cancer therapy.

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Section: Discussionsupporting

confidence: 64%

Elevated AEG-1 expression in macrophages promotes hypopharyngeal cancer invasion through the STAT3-MMP-9 signaling pathway

Liu

Zou

et al. 2016

Oncotarget

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“…28). Cell lines were authenticated by cell viability analysis, short tandem repeat profiling, and isoenzyme analysis.…”

Section: Cell Culturementioning

confidence: 99%

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

et al. 2017

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The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT þ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNg production, whereas CD155 overexpression inhibited T-cell metabolism and IFNg production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice.Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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“…Since these inflammatory mediators are also upregulated during aging, they may be driving AEG-1 expression during the aging process. Consequently, the fundamental participation of AEG-1 in inflammatory responses through the regulation of NF-κB pathway (Emdad et al , 2006; Li et al , 2014b; Sarkar et al , 2008) designates AEG-1 as a critical immune modulator in aging and age-related diseases (Fig. 3).…”

Section: Astrocytes and Aeg-1 In Agingmentioning

confidence: 99%

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

Vartak-Sharma

Nooka

Ghorpade

2017

Progress in Neurobiology

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Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, all hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington’s disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.

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Uncontrolled Inflammation Induced by AEG-1 Promotes Gastric Cancer and Poor Prognosis

Cited by 59 publications

References 48 publications

Elevated AEG-1 expression in macrophages promotes hypopharyngeal cancer invasion through the STAT3-MMP-9 signaling pathway

Elevated AEG-1 expression in macrophages promotes hypopharyngeal cancer invasion through the STAT3-MMP-9 signaling pathway

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

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