NRAGE Confers Radiation Resistance in 2D and 3D Cell Culture and Poor Outcome in Patients With Esophageal Squamous Cell Carcinoma

Zhou, Huandi; Wang, Guohui; Xiao, Zhiqing; Yu, Yang; Tian, Zhesen; Chen, Gao; Han, Xuetao; Sun, Wei; Hou, Liubing; Liu, Junling; Xue, Xiaoying

doi:10.3389/fonc.2022.831506

Cited by 7 publications

(4 citation statements)

References 55 publications

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“…Fatty acid synthase was conformed contributes to epithelial-mesenchymal transition and invasion of SACC through PRRX1/Wnt/β-catenin pathway ( 32 ). The overactivation of Wnt/β-catenin signaling pathway was found be associated with radioresistance of cervical cancer and esophageal squamous cell carcinoma, while its role in SACC radioresistance is still unclear and more research is needed ( 33 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

Silencing of AJAP1 expression by promoter methylation activates the Wnt/β-catenin signaling pathway to promote tumor proliferation and metastasis in salivary adenoid cystic carcinoma

Jiang¹,

Liu²,

Pan³

et al. 2023

Gland Surg

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Background Salivary adenoid cystic carcinoma (SACC) is a unique malignant tumor of the salivary gland with poor prognosis, which is not effective with chemotherapy and targeted drugs. Therefore, it is important to explore the molecular mechanism underlying SACC invasion and metastasis to develop novel therapeutic strategies and targets in clinical research. Methods Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were performed to detect the expression of Adherens Junctions Associated Protein 1 ( AJAP1 ). Methylation-specific PCR was used to evaluate the methylation of the AJAP1 promoter. AJAP1 was overexpressed or knocked down by lentivirus-mediated transfection. Kaplan-Meier analysis was conducted to create a survival curve and the log-rank test was used to analyze the overall survival (OS). The prognostic correlation was assessed using univariate and multivariate Cox regression analyses. Co-immunoprecipitation (Co-IP) was utilized to pull down the possible binding protein of AJAP1 and laser scanning confocal microscopy was applied to detect the subcellular localization of AJAP1 , E-cadherin, and β-catenin. Cell viability, colony formation, wound healing, and Transwell invasion assays were performed to evaluate the function of AJAP1 in vitro . A subcutaneous xenograft assay in nude mice was performed to verify the function of AJAP1 in vivo . Results AJAP1 was downregulated in SACC tumors and was closely related to SACC lymph node/distant metastasis, which was an independent risk factor for SACC prognosis. Methylation-specific PCR confirmed that high methylation of the AJAP1 promoter was the main cause of its silencing. Overexpression or knockdown of AJAP1 in SACC cells could significantly inhibit or promote the proliferation, invasion, and metastasis of SACC cells, respectively, in both the in vitro and in vivo experiments. Mechanically, we found that AJAP1 binds to E-cadherin and β-catenin to form a complex in cytomembrane, reducing the nuclear translocation of β-catenin and blocking the Wingless/Integrated/β-catenin (Wnt/β-catenin) signaling pathway to play a suppressive role in cancer. Conclusions In conclusion, these results suggest that the downregulation of AJAP1 protein expression may play a certain role in progression and metastasis of SACC. Our study indicates that AJAP1 may be a potential prognostic molecular marker and therapeutic target for SACC.

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Section: Discussionmentioning

confidence: 99%

Silencing of AJAP1 expression by promoter methylation activates the Wnt/β-catenin signaling pathway to promote tumor proliferation and metastasis in salivary adenoid cystic carcinoma

Jiang¹,

Liu²,

Pan³

et al. 2023

Gland Surg

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“…The expression of three biomarkers was detected by the IHC method as described in the instructions of ZSGB-BIO (PV-9000, Beijing, China). The immunohistochemical staining score was based on previously published articles ( 13 , 14 ). The staining estimation was assessed by the ImageJ software (National Institutes of Health).…”

Section: Methodsmentioning

confidence: 99%

Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy

Zhou

Lin²,

Yang³

et al. 2023

Front. Immunol.

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BackgroundThe study aimed to identify core biomarkers related to diagnosis and immune microenvironment regulation and explore the immune molecular mechanism of diabetic nephropathy (DN) through bioinformatics analysis.MethodsGSE30529, GSE99325, and GSE104954 were merged with removing batch effects, and different expression genes (DEGs) were screened at a criterion |log2FC| >0.5 and adjusted P <0.05. KEGG, GO, and GSEA analyses were performed. Hub genes were screened by conducting PPI networks and calculating node genes using five algorithms with CytoHubba, followed by LASSO and ROC analysis to accurately identify diagnostic biomarkers. In addition, two different GEO datasets, GSE175759 and GSE47184, and an experiment cohort with 30 controls and 40 DN patients detected by IHC, were used to validate the biomarkers. Moreover, ssGSEA was performed to analyze the immune microenvironment in DN. Wilcoxon test and LASSO regression were used to determine the core immune signatures. The correlation between biomarkers and crucial immune signatures was calculated by Spearman analysis. Finally, cMap was used to explore potential drugs treating renal tubule injury in DN patients.ResultsA total of 509 DEGs, including 338 upregulated and 171 downregulated genes, were screened out. “chemokine signaling pathway” and “cell adhesion molecules” were enriched in both GSEA and KEGG analysis. CCR2, CX3CR1, and SELP, especially for the combination model of the three genes, were identified as core biomarkers with high diagnostic capabilities with striking AUC, sensitivity, and specificity in both merged and validated datasets and IHC validation. Immune infiltration analysis showed a notable infiltration advantage for APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. In addition, the correlation analysis showed that CCR2, CX3CR1, and SELP were strongly and positively correlated with checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. Finally, dilazep was screened out as an underlying compound for DN analyzed by CMap.ConclusionsCCR2, CX3CR1, and SELP are underlying diagnostic biomarkers for DN, especially in their combination. APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation may participate in the occurrence and development of DN. At last, dilazep may be a promising drug for treating DN.

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“…NRAGE is a melanoma antigen-encoding gene homolog that interacts with neurotrophin-receptors to encode cancer-related proteins. Recent studies have confirmed that IR may promote NRAGE upregulation, which further triggers β-catenin nuclear protein accumulation, induces ESCC cell proliferation and cell cycle rearrangement, and then stimulates procancer activity [ 139 ]. Therefore, targeting the Wnt/β-catenin pathway is expected to result in prolonged OS and PFS in ESCC patients treated with IR, significantly improving prognosis.…”

Section: Reversal Strategy Of Escc Radioresistancementioning

confidence: 99%

Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma

An,

Li,

Jia

2023

Mol Cancer

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Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radioresistance is the major cause of disease progression and mortality in cancer, and it is associated with heterogeneity. Therefore, a better understanding of the radioresistance mechanisms may generate more reversal strategies to improve the cure rates and survival periods of ESCC patients. We mainly summarized the possible mechanisms of radioresistance in order to reveal new targets for ESCC therapy. Then we summarized and compared the current strategies to reverse radioresistance.

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NRAGE Confers Radiation Resistance in 2D and 3D Cell Culture and Poor Outcome in Patients With Esophageal Squamous Cell Carcinoma

Cited by 7 publications

References 55 publications

Silencing of AJAP1 expression by promoter methylation activates the Wnt/β-catenin signaling pathway to promote tumor proliferation and metastasis in salivary adenoid cystic carcinoma

Silencing of AJAP1 expression by promoter methylation activates the Wnt/β-catenin signaling pathway to promote tumor proliferation and metastasis in salivary adenoid cystic carcinoma

Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy

Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma

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