High A20 expression negatively impacts survival in patients with breast cancer

Yoon, Chung Sik; Ahn, Sung Gwe; Bae, Soong June; Shin, Yun Chang; Cha, Chihwan; Park, So Eun; Lee, Ji Hyung; Ooshima, Akira; Lee, Hye Sun; Yang, Kyung Min; Kim, Seong‐Jin; Park, Seok Hee; Lee, Jeong Eon

doi:10.1371/journal.pone.0221721

Cited by 18 publications

(26 citation statements)

References 36 publications

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“…Previous studies have suggested that effector T cell-derived IFNγ contributes to high levels of PD-1 expression in the tumor microenvironment ( 42 ); CCL2 attracts monocytes, increases the number of tumor-associated macrophages and promotes angiogenesis in breast cancer ( 43 ). Overexpression of CXCL10 is considered to be a favorable prognostic factor in TNBC ( 44 ), and high levels of TNFAIP3 expression are correlated with poor overall survival in HER2 + breast cancer and TNBC ( 45 ). We observed a close relationship between these hub genes and neutrophil infiltration in breast cancer tissue, suggesting that IL-17 cytokines attract and activate neutrophils by stimulating the production of neutrophilic chemokines.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

et al. 2020

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Background: The relationship between the interleukin 17 (IL-17) family of cytokines and breast cancer has been widely studied in recent years. Many studies have revealed increased levels of the cytokine IL-17A in estrogen receptor (ER)-negative or triple-negative breast cancer. Upregulation of IL-17A signaling is associated with increased expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in breast cancer with low ER expression and may elevate the infiltration of CD8 + T cells in tumor tissue. This study aims to determine whether ER downregulates the expression of PD-1/PD-L1, reduces the infiltration of CD8 + T cells, and affects the immune microenvironment by decreasing T-helper 17 (Th17) cell infiltration and inhibiting IL-17 signaling in breast cancer. Methods: Samples in The Cancer Genome Atlas Breast Cancer dataset were grouped by ER status and the PAM50 intrinsic subtype. The expression of IL-17 family cytokines and Th17 cell signature cytokines were compared between groups. IL-17 signaling pathway-related genes that were differentially expressed according to the ER level were identified. The PD-1 and PD-L1 levels were compared between breast cancer samples with different ER statuses and IL-17A/IL-17F expression levels. Correlation analyses of the expression of PD-1/PD-L1 and IL-17 signaling pathway-related genes were performed. The associations of the expression of IL-17 signaling pathway-related genes with the immune microenvironment were investigated. Results: High levels of ER decreased the expression of IL-17A, IL-17C, and IL-17F but increased the expression of IL-17E (IL25), which acts as a suppressor of IL-17 signaling. The expression levels of Th17 cell signature cytokines were significantly increased in ER-negative breast cancer. The expression levels of genes encoding downstream products of IL-17A/IL-17F signaling were downregulated in breast cancer with high ER expression. Increased expression of PD-1/PD-L1 was associated with ER-negative status, IL-17A-positive status, IL-17F-positive status, and upregulation of IL-17 signaling pathway-related genes in breast cancer. Enhanced IL-17 signal transduction was Shuai et al. Effect of ER in BC associated with the elevation of CD8 + T cell infiltration and variation of the immune microenvironment of breast cancer. Conclusion: High estrogen receptor levels decrease PD-1/PD-L1 expression and CD8 + T cell infiltration by suppressing Th17 cell infiltration and IL-17 signal transduction in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

et al. 2020

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“…In the present study, we observe upregulated expression levels of CXCR4, A20, and Snail1 in basal-like TNBC cells, suggesting that these proteins might be involved in the stabilization of Snail1. A20 is known to promote the stability of Snail1 through its monoubiquitination of Snail1 [ 45 , 57 ]. Nuclear pS473-Akt is an active serine kinase that stabilizes Snail1 through the inactivating phosphorylation of nuclear GSK-3β on S9.…”

Section: Discussionmentioning

confidence: 99%

Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

Subramaniyan

Sridharan

Howard

et al. 2020

Cancers

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The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.

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“…However, it is worth to be noted that the function of TNFAIP3 varies, as a tumor enhancer or suppressor, depending on different cancer context 29,30,32 . For example, TNFAIP3 is overexpressed in breast cancer, associated with breast cancer aggressiveness and poor prognosis of breast cancer patients 29 . TNFAIP3 mediates TNF-α promoted triple negative breast cancer aggressiveness, and its absence leads to cell apoptosis 33 .…”

Section: Discussionmentioning

confidence: 99%

TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

Chen

Gao²,

et al. 2020

Preprint

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Background: The ubiquitin-editing enzyme TNF inducible protein 3 (TNFAIP3) is a crucial regulator of inflammation and immunity. It is also involved in tumorigenesis of various cancers such as lymphomas, colorectal tumors and breast cancer. In this study, we aimed to explore the role and regulatory mechanism of TNFAIP3 in lung cancer. Methods: The expression of TNFAIP3 was determined in the Cancer Genome Atlas (TCGA) database. The levels of TNFAIP3 in lung cancer tissues was determined by immunohistochemistry (IHC) assay. TNFAIP3 knockdown and overexpression were performed, followed by further evaluation of cell viability, cell cycle and apoptosis. Cell cycle and apoptosis were observed by using flow cytometry and the key regulatory proteins were detected by western blotting. Colony formation assessment and EdU assay were adopted to check cell proliferation. Results: TNFAIP3 expression was downregulated in lung cancer tissues at both mRNA and protein levels, comparing with that in adjacent non-tumor tissues. Consequently, the colony formation ability of lung cancer cells was enhanced, and the number of EdU positive lung cancer cells was increased. By contrast, elevated TNFAIP3 expression resulted in decreased colony formation ability of lung cancer cells. Mechanistically, TNFAIP3 overexpression rendered cell cycle of lung cancer cells halted at G0/G1 phase and caused apoptosis of lung cancer cells.Conclusion: Our data suggested that TNFAIP3 exhibits tumor suppressive roles in lung cancer.

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High A20 expression negatively impacts survival in patients with breast cancer

Cited by 18 publications

References 36 publications

Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

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High A20 expression negatively impacts survival in patients with breast cancer

Cited by 18 publications

References 36 publications

Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer

Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

TNFAIP3&nbsp;Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

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TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis