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TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration.

ABSTRACT: Clinical and experimental evidence indicates that macrophages could promote solid-tumor progression and metastasis. However, the mechanisms underlying this process remain unclear. Here we show that yes-associated protein 1 (YAP1), a transcriptional regulator that controls tissue growth and regeneration, has an important role in tumor necrosis factor α (TNF α)-induced breast cancer migration. Mechanistically, macrophage conditioned medium (CM) or TNFα triggers IκB kinases (IKKs)-mediated YAP phosphorylation and activation in breast cancer cells. We further found that TNFα or macrophage CM treatment increases the interaction between p65 and YAP. Chromatin immunoprecipitation (ChIP) assay shows that YAP/TEAD (TEA domain family member) and p65 proteins synergistically regulate the transcription of hexokinase 2 (HK2), a speed-limiting enzyme in glycolysis, and promotes TNFα-induced or macrophage CM-induced cell migration. Together, our findings indicate an important role of TNFα-IKK-YAP/p65-HK2 signaling axis in the process of inflammation-driven migration in breast cancer cells, which reveals a new molecular link between inflammation and breast cancer metastasis.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5623908 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration.

Gao Y Y Yang Y Y Yuan F F Huang J J Xu W W Mao B B Yuan Z Z Bi W W

Oncogenesis 20170925 9

Clinical and experimental evidence indicates that macrophages could promote solid-tumor progression and metastasis. However, the mechanisms underlying this process remain unclear. Here we show that yes-associated protein 1 (YAP1), a transcriptional regulator that controls tissue growth and regeneration, has an important role in tumor necrosis factor α (TNF α)-induced breast cancer migration. Mechanistically, macrophage conditioned medium (CM) or TNFα triggers IκB kinases (IKKs)-mediated YAP phos ...[more]

PMID: 28945218

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Project description:BackgroundBreast cancer (BC) remains the most prevalent malignancy and the leading cause of cancer death. Circular RNAs (circRNAs) have been discovered to serve as crucial regulators in BC. In the current work, we aimed to study the impact of circRAD18 (hsa_circ_0002453) on BC progression and mechanism governing it.Materials and MethodsThe expression levels of circRAD18, miR-613 and hexokinase 2 (HK2) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). CircRAD18 identification was performed using RNase R digestion and actinomycin D assay. Cell viability, colony formation, apoptosis, migration, invasion and glycolysis were measured by Cell Counting Kit-8 assay, colony formation assay, flow cytometry, transwell analysis and extracellular acidification rate detection assay, respectively. Western blot was used to assess the levels of E-Cadherin, Vimentin, N-Cadherin and HK2 protein. The targeted interplay between miR-613 and circRAD18 or HK2 was detected by dual-luciferase reporter assay. Xenograft model assay was performed to observe the role of circRAD18 in vivo.ResultsCircRAD18 was highly expressed in BC tissues and cells. CircRAD18 depletion hindered BC cell malignant behaviors, as evidenced by the inhibition in cell viability, colony formation, migration, invasion, epithelial to mesenchymal transition and glycolysis, as well as the promotion in cell apoptosis. CircRAD18 directly interacted with miR-613, and miR-613 mediated the repressive effect of circRAD18 knockdown on BC cell malignant behaviors. Moreover, HK2 was a direct target of miR-613, and circRAD18 positively regulated HK2 expression via sponging miR-613. Additionally, circRAD18 knockdown repressed tumor growth in vivo by miR-613.ConclusionOur current work suggested that circRAD18 silencing suppressed BC cell malignant behaviors in vitro and tumor growth in vivo at least partly via the regulation of the miR-613/HK2 axis, highlighting that circRAD18 might be a promising therapeutic target for BC treatment.

Project description:BackgroundYes-associated protein (YAP) is a crucial mechanosensor involved in mechanotransduction, but its role in regulating mechanical force-induced bone remodeling during orthodontic tooth movement (OTM) is unclear. This study aims to elucidate the relationship between mechanotransduction and mechanical force-induced alveolar bone remodeling during OTM.ResultsOur study confirms an asynchronous (temporal and spatial sequence) remodeling pattern of the alveolar bone under mechanical force during OTM. Both compression and tension activate osteoclasts recruiting to the alveolar bone, whereas no significant presence of osteoblasts in the alveolar bone at the early stages of bone remodeling. Specifically, applying different force magnitudes (10, 25, 50, 100 g) to rats' 1st molars affected OTM distance. Force-induced alveolar bone remodeling was characterized by osteoclastogenesis and YAP activation at compressive/tensile sites on day 1 of OTM. Notably, 25 g force triggered peak YAP expression and osteoclastic activity early on. Time-course analysis revealed two YAP activity peaks on day1 and 14, contrasting with one peak of type I collagen expression on day14. In addition, RNA-sequencing highlighted increased nuclear factor kappa B (NF-κB) signaling, mineral absorption, and osteoclast differentiation at day-1 and 3. Moreover, gene expression analysis showed similar trends for NF-κB p65, YAP1, and TEA domain 1 (TEAD1) during this time. Furthermore, experiments on osteoclast cultures indicated YAP activation via large tumor suppressor (LATS) and TEAD under mechanical stimuli (compression/tension), promoting osteoclastogenesis by regulating NF-κB p65 and receptor activator of NF-κB (RANK). Inhibiting YAP with verteporfin delayed OTM by impairing force-induced osteoclastic activities in vivo and ex-vivo.ConclusionsWe propose that YAP mediates alveolar bone remodeling through NF-κB p65-induced osteoclastogenesis in an asynchronous remodeling pattern during OTM. Both compression and tension activate osteoclasts recruiting to the alveolar bone at early stages of bone remodeling, offering evidence for orthodontists as a reference.

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TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration.

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TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration.

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