<i>Gprc5a</i>-deficiency confers susceptibility to endotoxin-induced acute lung injury via NF-κB pathway

Liao, Yueling; Song, Hui; Xu, Danfeng; Jiao, Huike; Yao, Feng; Liu, Jingyi; Wu, Yadi; Zhong, Shuangshuang; Yin, Huijuan; Liu, Shuli; Wang, Xiaofei; Guo, Wenzheng; Sun, Beibei; Han, Baohui; Chinn, Y. Eugene; Deng, Jiong

doi:10.1080/15384101.2015.1006006

Cited by 22 publications

(25 citation statements)

References 35 publications

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“…Previous studies failed to induce neoplasia and fibrosis in experimental model by silica-exposure, which was probably due to the insensitivity or low response of wild-type mice. Thus, application of Gprc5a −/− mice in this study is important, which ensures that the pathological effects induced by silica exposure was greatly amplified or accelerated since Gprc5a −/− mice are susceptible to lung tumorigenesis [ 15 , 16 , 23 ] and endotoxin-induced lung injury [ 18 ]. In another word, Gprc5a mouse model overcomes the limitation of experiment performed in wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, increased M2 macrophages in lungs of silica-exposed Gprc5a −/− mice is consistent with increased tissue damages and fibrogenic response in these tissues. Previously, in the model of endotoxin-induced acute lung injury (ALI), NF-κB target gene expression was greatly activated in lungs from Gprc5a −/− mice compared to wild-type ones following administration of endotoxin, with a peak of activation within 2–24 hour [ 18 ]. However in this study, the mouse model is silica-induced lung injury, in which the samples of lung tissues were collected three months after silica exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Gprc5a -knockout ( Gprc5a −/− ) mice develop spontaneous lung tumors and are more susceptible than wild-type mice to development of eosinophilic macrophage pneumonia [ 16 ]. Moreover, Gprc5a −/− mice were sensitive to inflammation-promoted lung tumorigenesis and endotoxin-induced acute lung injury [ 17 , 18 ]. Thus, the causal relationship between silica exposure and neoplasia may be reproduced in Gprc5a −/− mouse model that is susceptible to both pulmonary inflammation and lung tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure

Wang

Liao

et al. 2015

Oncotarget

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Exposure to crystalline silica is suggested to increase the risk for a variety of lung diseases, including fibrosis and lung cancer. However, epidemiological evidences for the exposure-risk relationship are ambiguous and conflicting, and experimental study from a reliable animal model to explore the relationship is lacking. We reasoned that a mouse model that is sensitive to both lung injury and tumorigenesis would be appropriate to evaluate the exposure-risk relationship. Previously, we showed that, Gprc5a−/− mice are susceptible to both lung tumorigenesis and endotoxin-induced acute lung injury. In this study, we investigated the biological consequences in Gprc5a−/− mouse model following silica exposure. Intra-tracheal administration of fine silica particles in Gprc5a−/− mice resulted in more severe lung injury and pulmonary inflammation than in wild-type mice. Moreover, an enhanced fibrogenic response, including EMT-like characteristics, was induced in the lungs of Gprc5a−/− mice compared to those from wild-type ones. Importantly, increased hyperplasia or neoplasia coincided with silica-induced tissue injury and fibrogenic response in lungs from Gprc5a−/− mice. Consistently, expression of MMP9, TGFβ1 and EGFR was significantly increased in lungs from silica-treated Gprc5a−/− mice compared to those untreated or wild-type ones. These results suggest that, the process of tissue repair coincides with tissue damages; whereas persistent tissue damages leads to abnormal repair or neoplasia. Thus, silica-induced pulmonary inflammation and injury contribute to increased neoplasia development in lungs from Gprc5a−/− mouse model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure

Wang

Liao

et al. 2015

Oncotarget

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“…Gprc5a-knockout (ko) mice developed spontaneous lung adenocarcinoma [26,27], indicating that Gprc5a is a lung tumor suppressor gene. Importantly, tumorigenesis in Gprc5a-ko mouse lung is associated with inflammation along with persistent activation of NF-κB, EGFR, and STAT3 signaling [26][27][28], which resembles the pathological features in human lung cancer. Moreover, GPRC5A is repressed in most of NSCLC and all of chronic obstructive pulmonary disease (COPD) [29].…”

Section: Introductionmentioning

confidence: 90%

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Wang

Jing

et al. 2020

Oncogene

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Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE 2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE 2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE 2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE 2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE 2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.

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“…Here we demonstrated that GPRC5A activates NF-jB pathway in colorectal cancer which is opposite from our previously study that GPRC5A inhibits NF-jB activation in lung injury and tumorigenesis. 20 It suggests that may due to GPRC5A differently regulates the same pathway in tissue type specific manner. As the lung and the digestive tract are the two major tissues with high GPRC5A expression in healthy mouse and humans, it will be interesting to explore the mechanism through which Gprc5a plays dual roles in tumorigenesis in different tissues.…”

Section: Discussionmentioning

confidence: 99%

Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN‐1 induced oxidative stress

Zhang

Gao

et al. 2017

Intl Journal of Cancer

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The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here, we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-κB mediated Vanin-1 expression which is the predominant enzyme for cysteamine generation. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited γ-GCS activity, leading to reduction of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues.

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Gprc5a-deficiency confers susceptibility to endotoxin-induced acute lung injury via NF-κB pathway

Cited by 22 publications

References 35 publications

Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure

Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN‐1 induced oxidative stress

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