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TNF-? increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-?B pathway.

ABSTRACT: Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-?), promote BCSCs. However, the mechanism by which TNF-? promotes BCSCs is unclear. In this study, we demonstrate that TNF-? up-regulates TAZ, a transcriptional co-activator promoting BCSC self-renewal capacity in human breast cancer cell lines. Depletion of TAZ abrogated the increase in BCSCs mediated by TNF-?. TAZ is induced by TNF-? through the non-canonical NF-?B pathway, and our findings suggest that TAZ plays a crucial role in inflammatory factor-promoted breast cancer stemness and could serve as a promising therapeutic target.

SUBMITTER: Liu W

PROVIDER: S-EPMC7000832 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway.

Liu Wenjing W Lu Xiaoqing X Shi Peiguo P Yang Guangxi G Zhou Zhongmei Z Li Wei W Mao Xiaoyun X Jiang Dewei D Chen Ceshi C

Scientific reports 20200204 1

Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-α), promote BCSCs. However, the mechanism by which TNF-α promotes BCSCs is unclear. In this study, we demonstrate that TNF-α up-regulates TAZ, a transcriptional co-activator promoting BCSC self-renewal capacity in human breast cancer cell lines. Depl ...[more]

PMID: 32019974

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Project description:BackgroundAccelerated cellular senescence within the nucleus pulposus (NP) region is a common feature of disc degeneration. Our previous work indicated that TNF-α promoted NP cell senescence. Although the intervertebral disc has been reported to be an estrogen-sensitive tissue, it is unclear whether estrogen can inhibit premature senescence of NP cells.ObjectiveTo investigate whether 17beta-estradiol (E2) can attenuate TNF-α-induced premature senescence of NP cells and the potential mechanism behind this regulatory process.MethodsIsolated NP cells and intact intervertebral discs from healthy rats were cultured with or without TNF-α, E2 or their combination. The pan estrogen receptor (ER) antagonist ICI 182780 was used to investigate the role of ER. Direct and indirect indicators including cell proliferation, SA-β-Gal activity, telomerase activity, cell cycle, and the expression of matrix macromolecules (aggrecan and collagen II) and senescence markers (p16 and p53) were used to evaluate the premature senescence of NP cells. Additionally, intracellular reactive oxygen species (ROS) and NF-κB/p65 activity were also detected in the NP cell cultures.ResultsIn the NP cell cultures, E2 significantly increased cell proliferation potency, telomerase activity and the expression of matrix macromolecules but attenuated SA-β-Gal activity, senescence marker (p53 and p16) expression and G1 cycle arrest in TNF-α-treated NP cells. Furthermore, E2 inhibited ROS generation and phospho-NF-κB/p65 expression in the TNF-α-treated NP cells. However, the ER antagonist ICI 182780 abolished the effects of E2 on TNF-α-treated NP cells. In the disc organ cultures, E2 also significantly increased matrix synthesis, whereas it decreased senescence marker (p53 and p16) expression, which could be abolished by the ER antagonist ICI 182780.ConclusionThe interaction between E2 and ER can attenuate TNF-α-induced premature senescence of rat NP cells through interfering with the ROS/NF-κB pathway.

Project description:Background and aim: Pro-inflammatory macrophages aggravated progress of pulmonary fibrosis (PF) both in patients and animal models. Fuzheng Huayu (FZHY) formula, a Chinese herbal product, is effective in treating pulmonary fibrosis in our previous study. But its action mechanism against PF relating to macrophage activation was unclear. This study was designed to evaluate the anti-fibrotic and anti-inflammatory roles of FZHY in pulmonary fibrosis and to elucidate the potential mechanisms. Methods: Network pharmacology was employed to identify the interrelationships among compounds of FZHY, potential targets and putative pathways on anti-pulmonary fibrosis. According to the data of bioinformatics analysis, the key pharmacological target for FZHY against PF was screened. The network pharmacological prediction was validated by a series of experimental assays, including CCK8, western blot and immunofluorescence staining. Then molecular mechanism of FZHY on relating to the predictive target were studied in bleomycin induced pulmonary fibrosis in mice with methylprednisolone as a positive control, and in lipopolysaccharide (LPS) stimulated cultured macrophages in culture, respectively. Results: The network pharmacology analysis reveal that a total of 12 FZHY-PF crossover proteins were filtered into a protein-protein interaction network complex and designated as the potential targets of FZHY against pulmonary fibrosis, while TNF-α signal pathway ranked at the top. FZHY and methylprednisolone could attenuate the lung fibrosis and decrease pulmonary TNF-α expression in bleomycin induced fibrotic mice, without difference between two treatments. While TNF-α was mainly originated from macrophages identified by double fluorescent staining of TNF-α and F4/80. LPS stimulated cultured macrophage polarization and activation demonstrated by the enhance contents of TNF-α and iNOS but decreased level of Arg-1. FZHY could alleviate the LPS stimulated macrophage polarization and activation demonstrated by decreasing TNF-α and iNOS and increasing Arg-1. In particular, FZHY could significantly reduce the production of p65 and the nuclear translocation of phosphorylated p65. Conclusion: Fuzheng Huayu formula has a good effect against pulmonary fibrosis induced by bleomycin in mice, whose action mechanism was associated with down-regulation of NF-κB/TNF-α signaling pathway in pro-inflammatory macrophages. These findings provided an important strategy for developing new agents against lung fibrosis and accelerated FZHY product application on patients with lung fibrosis.

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TNF-? increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-?B pathway.

Publications

TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway.

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