The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells

Anderson, Alison; Kalimutho, Murugan; Harten, Sarah K.; Nanayakkara, Devathri; Khanna, Kum Kum; Ragan, Mark A.

doi:10.1038/srep39873

Cited by 27 publications

(26 citation statements)

References 52 publications

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“…6). Further studies identifying an endogenous inhibitor of the iP in astrocytes [67] are needed to yield a potential therapeutic target for SPMS and PPMS patients.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was collected from human brainstem and spinal cord astrocytes (ScienCell) using a RNeasy Kit (QIAGEN) according to manufacturer's instructions. Reverse transcription and SYBR Green qRT-PCR were performed as previously described [65,66] for constitutive and immunoproteasome subunits using established primers [67]. Transcript levels were normalized to copies of GAPDH.…”

Section: Qrt-pcr Analysismentioning

confidence: 99%

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The impact of regional astrocyte interferon-γ signaling during chronic autoimmunity: a novel role for the immunoproteasome

Smith

Sinyuk

Jenkins

et al. 2020

J Neuroinflammation

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Background: In early autoimmune neuroinflammation, interferon (IFN)γ and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNγ has protective properties. Although dysregulation of the iP has been implicated in neurodegeneration, its function remains to be fully elucidated. Here, we demonstrate that IFNγ signaling in regional astrocytes induces the iP and promotes protection of the CNS during chronic autoimmunity. Methods: In a multiple sclerosis (MS) brain, we evaluated mRNA expression and labeled postmortem MS brainstem and spinal cord for iP subunits and indicators of oxidative stress. Primary regional human astrocytes were analyzed for iP regulation and function by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, OxyBlot, and reactive oxygen species and caspase activity detection assays. Following immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 , the role of IFNγ signaling and the iP during chronic experimental autoimmune encephalomyelitis (EAE) were assessed using pharmacologic inhibition of the iP and genetic interruption of IFNγ signaling specifically in astrocytes. Central nervous system (CNS) tissues were analyzed by immunohistochemistry (IHC) and immunofluorescence, and cell-specific colocalization was quantified. Results: In MS tissue, iP expression was enhanced in the spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress. In vitro, IFNγ stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, EAE, ONX 0914 treatment exacerbated the disease and led to increased oxidative stress and polyubiquitinated protein buildup. Finally, mice with astrocyte-specific loss of the IFNγ receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress, and poly-ubiquitinated protein accumulation in astrocytes. Conclusions: Taken together, our data reveal a protective role for IFNγ in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.

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“…6). Further studies identifying an endogenous inhibitor of the iP in astrocytes [67] are needed to yield a potential therapeutic target for SPMS and PPMS patients.…”

Section: Discussionmentioning

confidence: 99%

Section: Qrt-pcr Analysismentioning

confidence: 99%

The impact of regional astrocyte interferon-γ signaling during chronic autoimmunity: a novel role for the immunoproteasome

Smith

Sinyuk

Jenkins

et al. 2020

J Neuroinflammation

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“…IPA results helped us in finding cellular functions and several pathways and networks related to RSS. It has been reported that five top upstream regulators, namely, PDE4B, LILRB4, RARRES3, IFNL4, TICAM1, are associated with colorectal cancer [ 23 ], leukemia [ 24 ], breast cancer [ 25 ], prostate cancer [ 26 ], and thyroid cancer [ 27 ], respectively. These regulators seem to be associated with radiosensitivity in some ways.…”

Section: Discussionmentioning

confidence: 99%

Gene signature for prediction of radiosensitivity in human papillomavirus-negative head and neck squamous cell carcinoma

et al. 2020

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The probability of recurrence of cancer after adjuvant or definitive radiotherapy in patients with human papillomavirus-negative (HPV(-)) head and neck squamous cell carcinoma (HNSCC) varies for each patient. This study aimed to identify and validate radiation sensitivity signature (RSS) of patients with HPV(-) HNSCC to predict the recurrence of cancer after radiotherapy. Materials and Methods: Clonogenic survival assays were performed to assess radiosensitivity in 14 HNSCC cell lines. We identified genes closely correlated with radiosensitivity and validated them in The Cancer Genome Atlas (TCGA) cohort. The validated RSS were analyzed by ingenuity pathway analysis (IPA) to identify canonical pathways, upstream regulators, diseases and functions, and gene networks related to radiosensitive genes in HPV(-) HNSCC. Results: The survival fraction of 14 HNSCC cell lines after exposure to 2 Gy of radiation ranged from 48% to 72%. Six genes were positively correlated and 35 genes were negatively correlated with radioresistance, respectively. RSS was validated in the HPV(-) TCGA HNSCC cohort (n = 203), and recurrence-free survival (RFS) rate was found to be significantly lower in the radioresistant group than in the radiosensitive group (p = 0.035). Cell death and survival, cell-to-cell signaling, and cellular movement were significantly enriched in RSS, and RSSs were highly correlated with each other. Conclusion: We derived a HPV(-) HNSCC-specific RSS and validated it in an independent cohort. The outcome of adjuvant or definitive radiotherapy in HPV(-) patients with HNSCC can be predicted by analyzing their RSS, which might help in establishing a personalized therapeutic plan.

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“…TGB-b signaling is one of the most important roles of EMT in breast cancer [59]. Proteasome subunit beta type-9 (PSMB9) is co-expressed with RARRES3 and is a well-known metastasis suppressor in breast cancer cells [60].…”

Section: Discussionmentioning

confidence: 99%

Estimation of 18F-FDG PET Image Texture Features for Metastasis Prediction in Non-Small Cell Lung Cancer Using Epithelial Mesenchymal Transition-Related Genes

Kim¹,

I²,

Bh³

et al. 2020

Preprint

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Purpose: The aim of this study was to estimate a metastasis prediction image factor in non-small cell lung cancer by correlation next generation sequence gene expression level and fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography image features.Methods: RNA-sequencing data and 18F-FDG PET images of 63 patients with NSCLC (29 metastasis and 34 non-metastasis) from The Cancer Imaging Archive and The Cancer Genome Atlas Program databases were used in a combined analysis. Weighted correlation network analysis was performed to identify gene groups were related metastasis. Module was selected with high module significance. Genes selection was performed by gene function related metastasis and high AUC (AUC > 0.6). A total of 47 image features were extracted from PET images as radiomics. The relationship of Gene expression and image features were calculated by using a hypergeometric distribution test with the Pearson correlation method. Metastasis prediction model was validated by random forest algorithm using image texture features related gene expression.Results: 36 modules were identified by gene expression pattern with WGCNA assay. The modules had highest module significance was selected assay. 7 genes from selected module were identified to involve in the epithelial mesenchymal transition pathway that have important role in the cancer metastasis and had high AUC. Also, expression of these genes was related to quantitative of image feature (GLCM_contrast, -log10 P-value: 2.45~3.89). The AUC value (accuracy: 0.856 ± 0.06, AUC: 0.868 ± 0.05) was shown from the EMT-related gene and GLCM_contrast model and AUC value (accuracy: 0.842 ± 0.06, AUC: 0.838 ± 0.09) was shown from GLCM_contrast image texture model. Conclusion: GLCM_contrast image texture feature shows relationship with EMT related gene expression. We developed a model for predicting metastasis of non-small cell lung cancer using 18F-FDG PET image feature and evaluated its accuracy.

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The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells

Cited by 27 publications

References 52 publications

The impact of regional astrocyte interferon-γ signaling during chronic autoimmunity: a novel role for the immunoproteasome

The impact of regional astrocyte interferon-γ signaling during chronic autoimmunity: a novel role for the immunoproteasome

Gene signature for prediction of radiosensitivity in human papillomavirus-negative head and neck squamous cell carcinoma

Estimation of 18F-FDG PET Image Texture Features for Metastasis Prediction in Non-Small Cell Lung Cancer Using Epithelial Mesenchymal Transition-Related Genes

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