Dataset Information

MiR-155-mediated loss of C/EBP? shifts the TGF-? response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer.

ABSTRACT: During breast cancer progression, transforming growth factor-beta (TGF-?) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBP?), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-?-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBP? was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBP? potentiated the TGF-? response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-?. Furthermore, loss of C/EBP? enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBP? promoted the TGF-? response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBP? as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBP? as a mechanism, which promotes breast cancer progression by shifting the TGF-? response from growth inhibition to EMT, invasion and metastasis.

SUBMITTER: Johansson J

PROVIDER: S-EPMC3898103 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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MiR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer.

Johansson J J Berg T T Kurzejamska E E Pang M-F MF Tabor V V Jansson M M Roswall P P Pietras K K Sund M M Religa P P Fuxe J J

Oncogene 20130819 50

During breast cancer progression, transforming growth factor-beta (TGF-β) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBPβ), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mamma ...[more]

PMID: 23955085

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Project description:Transforming growth factor (TGF)‑β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor‑derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF‑β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF‑β1 stimulated cervical cancer cells to secrete more miR‑663b‑containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR‑663b directly targets the 3'-untranslated regions (3'‑UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial‑mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR‑663b, causing increased expression of epithelial differentiation marker E‑cadherin and decreased expression of mesenchymal markers N‑cadherin and β‑catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR‑663b. Exosome PKH67‑labeling experiment verified that exosomal miR‑663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR‑663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real‑time transcription‑polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell‑derived exosomal miR‑663b is endocytosed by cervical cancer cells adjacent or distant after TGF‑β1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

Dataset Information

MiR-155-mediated loss of C/EBP? shifts the TGF-? response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer.

Publications

MiR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer.

Similar Datasets

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