Abstract
BackgroundThe communication between carcinoma associated fibroblasts (CAFs) and cancer cells facilitate tumor metastasis. In this study, we further underlying the epigenetic mechanisms of CAFs feed the cancer cells and the molecular mediators involved in these processes.MethodsMCF-7 and MDA-MB-231 cells were treated with CAFs culture conditioned medium, respectively. Cytokine antibody array, enzyme-linked immunosorbent assay, western blotting and immunofluorescence were used to identify the key chemokines. Chromatin immunoprecipitation and luciferase reporter assay were performed to explore the transactivation of target LncRNA by CAFs. A series of in vitro assays was performed with RNAi-mediated knockdown to elucidate the function of LncRNA. An orthotopic mouse model of MDA-MB-231 was conducted to confirm the mechanism in vivo.ResultsHere we reported that TGF-β1 was top one highest level of cytokine secreted by CAFs as revealed by cytokine antibody array. Paracrine TGF-β1 was essential for CAFs induced EMT and metastasis in breast cancer cells, which is a crucial mediator of the interaction between stromal and cancer cells. CAF-CM significantly enhanced the HOTAIR expression to promote EMT, whereas treatment with small-molecule inhibitors of TGF-β1 attenuated the activation of HOTAIR. Most importantly, SMAD2/3/4 directly bound the promoter site of HOTAIR, located between nucleotides -386 and -398, -440 and -452, suggesting that HOTAIR was a directly transcriptional target of SMAD2/3/4. Additionally, CAFs mediated EMT by targeting CDK5 signaling through H3K27 tri-methylation. Depletion of HOTAIR inhibited CAFs-induced tumor growth and lung metastasis in MDA-MB-231 orthotopic animal model.ConclusionsOur findings demonstrated that CAFs promoted the metastatic activity of breast cancer cells by activating the transcription of HOTAIR via TGF-β1 secretion, supporting the pursuit of the TGF-β1/HOTAIR axis as a target in breast cancer treatment.
Highlights
The communication between carcinoma associated fibroblasts (CAFs) and cancer cells facilitate tumor metastasis
Aberrant CDK5 promoter DNA hypomethylation was identified in the mantle cell lymphoma genome compared with normal naive B cells [25]. These findings indicate an interaction between CDK5 signaling and tumor stromal cells, which may underlie the novel epigenetic mechanism of tumor environment-induced metastasis and hold therapeutic potential in breast cancer. Based on these previous studies, we further demonstrated that CAFs promoted the metastasis of breast cancer cells via paracrine transforming growth factor β1 (TGF-β1), which is a crucial mediator of the interaction between stromal and cancer cells
Paracrine TGF-β1 was essential for CAFs to promote the metastasis of breast cancer cells During breast cancer progression, CAFs may supply appropriate signals that may promote the development of aggressive phenotypes in carcinoma cells and establish a complex scenario, which culminates in metastasis [26]
Summary
The communication between carcinoma associated fibroblasts (CAFs) and cancer cells facilitate tumor metastasis. We further underlying the epigenetic mechanisms of CAFs feed the cancer cells and the molecular mediators involved in these processes. Ren et al Molecular Cancer (2018) 17:5 been proven to be a major contributor of various processes, such as proliferation, invasion, angiogenesis and drug resistance [5,6,7] These effects are mediated by paracrine stimulation from a variety of growth factors and cytokines, including transforming growth factor β1 (TGF-β1), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and interleukins (IL) [8, 9]. The epigenetic mechanisms by which CAFs feed the cancer cells and allow them to acquire an aggressive phenotype and the molecular mediators involved in these processes have not been extensively studied
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