Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion

Molecular Cancer

Xuan Zhou¹  Yun-fei Wang²  Chun-sheng Kang²  Xiao-hui Zhao³  Xiu-lan Zhao⁴  Yan Dou⁵  Xin Song⁵  Zhi-yan Zhu⁵  Wei-ping Tian⁵  Yu Ren⁵  Yi-qi Xu⁵  Huan-huan Jia⁵  Mei Mei⁵  Ting Sun⁵ 

[1] Department of Head and Neck, Tianjin Medical University Cancer Hospital;Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro- oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City;Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital;Department of Pathology, Tianjin Medical University;Research Center of Basic Medical Sciences, Tianjin Medical University;

关键词: Carcinoma associated fibroblasts;    TGF-β1;    HOTAIR;    Epigenetic control;    Metastasis;   

DOI  :  10.1186/s12943-018-0758-4

来源: DOAJ

【 摘 要 】

Abstract Background The 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. Methods MCF-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. Results Here 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. Conclusions Our 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.

【 授权许可】

Unknown