Dataset Information

DDX19A Promotes Metastasis of Cervical Squamous Cell Carcinoma by Inducing NOX1-Mediated ROS Production.

ABSTRACT: The major obstacle to treat cervical squamous cell carcinoma (CSCC) is the high prevalence of metastasis, which severely affects 5-year survival rate and quality of life for cancer patients. The DEAD-box helicase family has been reported to be a critical mediator in the development and metastasis of various cancers. DEAD-box helicase 19A (DDX19A) is a member of the DEAD-box helicase family; however, its functional role in CSCC is unclear. In this study, bioinformatics analysis of clinical samples from public databases demonstrated that the expression of DDX19A was elevated in CSCC tissues and that high expression of DDX19A was positively correlated with metastasis and poor clinical outcome. Functionally, we found that DDX19A promoted CSCC cell migration and invasion in vitro and lung metastasis in vivo. Mechanistically, overexpression of DDX19A increased NADPH oxidase 1 (NOX1) expression, enhanced reactive oxygen species (ROS) production, and induced the migration and invasion of CSCC cells. Rescue experiments revealed that DDX19A-induced CSCC functional alterations were dependent on NOX1 and that DDX19A-promoted CSCC metastasis was abrogated upon the inhibition of ROS. Our results demonstrated that DDX19A could promote CSCC metastasis by inducing NOX1-mediated ROS production and that blockage of the NOX1/ROS axis might serve as a potential therapeutic target for patients with DDX19A-overexpressed CSCC.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC8100682 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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DDX19A Promotes Metastasis of Cervical Squamous Cell Carcinoma by Inducing NOX1-Mediated ROS Production.

Jiang Yanhui Y Wang Baibin B Li Yongliang Y Shen Jiahui J Wei Yutao Y Li Hanjie H Chen Shangqiu S Yang Hua H Zeng Famin F Liu Changqing C Wang Feng F He Huanhuan H Chen Yong Y Liu Jihong J

Frontiers in oncology 20210422

The major obstacle to treat cervical squamous cell carcinoma (CSCC) is the high prevalence of metastasis, which severely affects 5-year survival rate and quality of life for cancer patients. The DEAD-box helicase family has been reported to be a critical mediator in the development and metastasis of various cancers. DEAD-box helicase 19A (DDX19A) is a member of the DEAD-box helicase family; however, its functional role in CSCC is unclear. In this study, bioinformatics analysis of clinical sample ...[more]

PMID: 33968728

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Project description:BackgroundHepatocellular carcinoma (HCC) is the most major type of primary hepatic cancer. Serine hydroxymethyltransferase 1 (SHMT1) is recently found to play critical roles in human cancers including lung cancer, ovarian cancer and intestinal cancer. However, the expression, function and the underlying mechanisms of SHMT1 in HCC remain uncovered.MethodsqRT-PCR, immunohistochemistry and immunoblotting were performed to detect the expression of SHMT1 in HCC tissues and cell lines. HCC cell migration and invasion were determined by Boyden chamber and Transwell assay in vitro, and tumor metastasis was assessed via lung metastasis model in mice. The expression of key factors involved in epithelial-to-mesenchymal transition (EMT) process was evaluated by western blotting.ResultsIn this study, data mining of public databases and analysis of clinical specimens demonstrated that SHMT1 expression was decreased in HCC. Reduced SHMT1 level was correlated with unfavorable clinicopathological features and poor prognosis of HCC patients. Gain- and loss-of-function experiments showed that SHMT1 overexpression inhibited the migration and invasion of HCCLM3 cells while SHMT1 knockdown enhanced the metastatic ability of Hep3B cells. Furthermore, qRT-PCR and western blotting showed that SHMT1 inhibited EMT and matrix metallopeptidase 2 (MMP2) expression. In vivo experiments showed that SHMT1 suppressed the lung metastasis of HCC cells in mice. Mechanistically, SHMT1 knockdown enhanced reactive oxygen species (ROS) production, and thus promoted the motility, EMT and MMP2 expression in Hep3B cells. Furthermore, NADPH oxidase 1 (NOX1) was identified to be the downstream target of SHMT1 in HCC. NOX1 expression was negatively correlated with SHMT1 expression in HCC. Rescue experiments revealed that NOX1 mediated the functional influence of SHMT1 on HCC cells.ConclusionsThese data indicate that SHMT1 inhibits the metastasis of HCC by repressing NOX1 mediated ROS production.

Project description:BackgroundEvading immune surveillance is necessary for tumor metastasis. Thus, there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion. In this study, we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma (ESCC).MethodsThe expression of melanoma-associated antigen C3 (MAGE-C3) was detected using immunohistochemistry. Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma (ESCC) cells. Metastasis assays in mice were used to evaluate metastatic ability in vivo. Lymphocyte-mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells. RNA sequencing was performed to identify differentially expressed genes between MAGE-C3 overexpressing ESCC cells and control cells. Gene ontology (GO) enrichment analyses was performed to identify the most altered pathways influenced by MAGE-C3. The activation of the interferon-γ (IFN-γ) pathway was analyzed using Western blotting, GAS luciferase reporter assays, immunofluorescence, and flow cytometry. The role of MAGE-C3 in the IFN-γ pathway was determined by Western blotting and immunoprecipitation. Furthermore, immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.ResultsMAGE-C3 was overexpressed in ESCC tissues. High expression of MAGE-C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC. Functional experiments revealed that MAGE-C3 promoted tumor metastasis by activating the epithelial-mesenchymal transition (EMT). MAGE-C3 repressed antitumor immunity and regulated cytokine secretion of T cells, implying an immunosuppressive function. Mechanistically, MAGE-C3 facilitated IFN-γ signaling and upregulated programmed cell death ligand 1 (PD-L1) by binding with IFN-γ receptor 1 (IFNGR1) and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1 (STAT1). Interestingly, MAGE-C3 displayed higher tumorigenesis in immune-competent mice than in immune-deficient nude mice, confirming the immunosuppressive role of MAGE-C3. Furthermore, mice bearing MAGE-C3-overexpressing tumors showed worse survival and more lung metastases with decreased CD8+ infiltrated T cells and increased programmed cell death 1 (PD-1)+ CD8+ infiltrated T cells.ConclusionMAGE-C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance, and could be a potential prognostic marker and therapeutic target.

Dataset Information

DDX19A Promotes Metastasis of Cervical Squamous Cell Carcinoma by Inducing NOX1-Mediated ROS Production.

Publications

DDX19A Promotes Metastasis of Cervical Squamous Cell Carcinoma by Inducing NOX1-Mediated ROS Production.

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