Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion
0301 basic medicine
Epithelial-Mesenchymal Transition
Transcription, Genetic
Smad Proteins
Metastasis
Epigenesis, Genetic
Epigenetic control
Transforming Growth Factor beta1
Mice
03 medical and health sciences
HOTAIR
Cancer-Associated Fibroblasts
Cell Movement
TGF-β1
Cell Line, Tumor
Neoplasms
Paracrine Communication
Animals
Humans
Neoplasm Metastasis
RC254-282
Research
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Cyclin-Dependent Kinase 5
Prognosis
3. Good health
Carcinoma associated fibroblasts
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
RNA, Long Noncoding
Signal Transduction
DOI:
10.1186/s12943-018-0758-4
Publication Date:
2018-01-11T10:21:12Z
AUTHORS (14)
ABSTRACT
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.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.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.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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (40)
CITATIONS (158)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....