Mechanism of MEN1 gene in radiation-induced pulmonary fibrosis in mice

Wei, Wei; Zhang, Haiyang; Gong, Xinkou; Dong, Zuo-Ren; Chen, Zhiyuan; Wang, Rui; Yi, Junxuan; Shen, Yan; Jin, Shunzi

doi:10.1016/j.gene.2018.08.039

Cited by 9 publications

(11 citation statements)

References 29 publications

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“…The regimen was similar to that used for human therapy reflecting the understanding of the clinically related HDFR-mediated normal cell damage like fibrosis. Long-term effects (12 months) on diffuse region of the left lung and non-irradiated right lung after 20Gy IR which dose ranges (15–20 Gy) are frequently used as IR-induced lung fibrosis model [8–11] were also compared.…”

Section: Introductionmentioning

confidence: 99%

Identification of molecular signatures involved in radiation-induced lung fibrosis

et al. 2018

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In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose-limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non-irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region and neighboring region. Upregulation of gtse1 in both 90Gy-irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFβ or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggesting fibrosis responsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies.Key messages Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model.Gtse1 and Fgl1 are involved in radiation or TGFβ-induced epithelial-mesenchymal transition.Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1.Gtse1 and Fgl1 are suggested to be novel targets for radiation-induced lung fibrosis. Electronic supplementary materialThe online version of this article (10.1007/s00109-018-1715-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Identification of molecular signatures involved in radiation-induced lung fibrosis

et al. 2018

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“…In this study, we focused on the treatment for acute radiation injury. Radiation pneumonia usually occurs within the hours, days and weeks after exposure [ 27 ], radiation-induced pulmonary fibrosis can be observed after 4 weeks following radiation exposure [ 28 ]. Thus, we assessed the structure, function and inflammation of lung tissues in experimental mice at 21 days after irradiation.…”

Section: Discussionmentioning

confidence: 99%

Gut Microbiota-Derived PGF2α Fights against Radiation-Induced Lung Toxicity through the MAPK/NF-κB Pathway

et al. 2021

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Radiation pneumonia is a common and intractable side effect associated with radiotherapy for chest cancer and involves oxidative stress damage and inflammation, prematurely halting the remedy and reducing the life quality of patients. However, the therapeutic options for the complication have yielded disappointing results in clinical application. Here, we report an effective avenue for fighting against radiation pneumonia. Faecal microbiota transplantation (FMT) reduced radiation pneumonia, scavenged oxidative stress and improved lung function in mouse models. Local chest irradiation shifted the gut bacterial taxonomic proportions, which were preserved by FMT. The level of gut microbiota-derived PGF2α decreased following irradiation but increased after FMT. Experimental mice with PGF2α replenishment, via an oral route, exhibited accumulated PGF2α in faecal pellets, peripheral blood and lung tissues, resulting in the attenuation of inflammatory status of the lung and amelioration of lung respiratory function following local chest irradiation. PGF2α activated the FP/MAPK/NF-κB axis to promote cell proliferation and inhibit apoptosis with radiation challenge; silencing MAPK attenuated the protective effect of PGF2α on radiation-challenged lung cells. Together, our findings pave the way for the clinical treatment of radiotherapy-associated complications and underpin PGF2α as a gut microbiota-produced metabolite.

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“… 20 A recent study demonstrated that the levels of menin by degrees diminish with the progression of fibrosis in a mouse model of radiation‐induced pulmonary fibrosis. 21 The potential link between MEN1 expression and fibrosis provides a novel chance to reveal the biological function of MEN1 in renal fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…In terms of fibrotic disorders, an early study suggested that menin is a pivotal regulator of activated signalling networks in hepatic fibrogenesis 20 . A recent study demonstrated that the levels of menin by degrees diminish with the progression of fibrosis in a mouse model of radiation‐induced pulmonary fibrosis 21 . The potential link between MEN1 expression and fibrosis provides a novel chance to reveal the biological function of MEN1 in renal fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

Loss of MEN1 leads to renal fibrosis and decreases HGF‐Adamts5 pathway activity via an epigenetic mechanism

Jin

Zhu

Zhou

et al. 2022

Clinical & Translational Med

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Background Renal fibrosis is a serious condition that results in the development of chronic kidney diseases. The MEN1 gene is an epigenetic regulator that encodes the menin protein and its role in kidney tissue remains unclear. Methods Kidney histology was examined on paraffin sections stained with hematoxylin‐eosin staining. Masson’s trichrome staining and Sirius red staining were used to analyze renal fibrosis. Gene and protein expression were determined by quantitative real‐time PCR (qPCR) and Western blot, respectively. Immunohistochemistry staining in the kidney tissues from mice or patients was used to evaluate protein levels. Flow cytometry was used to analyze the cell cycle distributions and apoptosis. RNA‐sequencing was performed for differential expression genes in the kidney tissues of the Men1f/f and Men1∆/∆ mice. Chromatin immunoprecipitation sequencing (ChIP‐seq) was carried out for identification of menin‐ and H3K4me3‐enriched regions within the whole genome in the mouse kidney tissue. ChIP‐qPCR assays were performed for occupancy of menin and H3K4me3 at the gene promoter regions. Luciferase reporter assay was used to detect the promoter activity. The exacerbated unilateral ureteral obstruction (UUO) models in the Men1f/f and Men1∆/∆ mice were used to assess the pharmacological effects of rh‐HGF on renal fibrosis. Results The expression of MEN1 is reduce in kidney tissues of fibrotic mouse and human diabetic patients and treatment with fibrotic factor results in the downregulation of MEN1 expression in renal tubular epithelial cells (RTECs). Disruption of MEN1 in RTECs leads to high expression of α‐SMA and Collagen 1, whereas MEN1 overexpression restrains epithelial‐to‐mesenchymal transition (EMT) induced by TGF‐β treatment. Conditional knockout of MEN1 resulted in chronic renal fibrosis and UUO‐induced tubulointerstitial fibrosis (TIF), which is associated with an increased induction of EMT, G2/M arrest and JNK signaling. Mechanistically, menin recruits and increases H3K4me3 at the promoter regions of hepatocyte growth factor (HGF) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts5) genes and enhances their transcriptional activation. In the UUO mice model, exogenous HGF restored the expression of Adamts5 and ameliorated renal fibrosis induced by Men1 deficiency. Conclusions These findings demonstrate that MEN1 is an essential antifibrotic factor in renal fibrogenesis and could be a potential target for antifibrotic therapy.

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Mechanism of MEN1 gene in radiation-induced pulmonary fibrosis in mice

Cited by 9 publications

References 29 publications

Identification of molecular signatures involved in radiation-induced lung fibrosis

Identification of molecular signatures involved in radiation-induced lung fibrosis

Gut Microbiota-Derived PGF2α Fights against Radiation-Induced Lung Toxicity through the MAPK/NF-κB Pathway

Loss of MEN1 leads to renal fibrosis and decreases HGF‐Adamts5 pathway activity via an epigenetic mechanism

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