MicroRNA let-7a suppresses breast cancer cell migration and invasion through down-regulation of C-C chemokine receptor type 7
- Authors
- Kim, S.J., Shin, J.Y., Lee, K.D., Bae, Y.K., Sung, K.W., Nam, S.J., and Chun, K.H.
- ID
- ZDB-PUB-120125-10
- Date
- 2012
- Source
- Breast cancer research : BCR 14(1): R14 (Journal)
- Registered Authors
- Bae, Young Ki
- Keywords
- none
- MeSH Terms
-
- 3' Untranslated Regions
- Animals
- Base Sequence
- Binding Sites
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology*
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology*
- Cell Line, Tumor
- Cell Movement*
- Cell Proliferation
- Chemokine CCL21/genetics
- Chemokine CCL21/metabolism
- Down-Regulation*
- Female
- Gene Expression
- Gene Expression Regulation, Neoplastic
- Humans
- MicroRNAs/physiology*
- Neoplasm Invasiveness
- Neoplasm Transplantation
- RNA Interference
- Receptors, CCR7/genetics*
- Receptors, CCR7/metabolism
- Zebrafish
- PubMed
- 22251626 Full text @ Breast Cancer Res.
Introduction
C-C Chemokine receptor type7 (CCR7), plays an important role in chemotactic and metastatic responses in various cancers, including breast cancer. In this study, we demonstrated that microRNA Let-7a down-regulates CCR7 expression and directly influences the migration and invasion of breast cancer cells.
Methods
We detected the expressions of CCR7, its ligand CCL21, and Let-7a in breast cancer cell lines and in breast cancer patient tissues. We used synthetic Let-7a oligo-nucleotides and inhibitor of Let-7a and transfection into respective MDA-MB-231 and MCF-7 breast cancer cells and performed the cell proliferation, cell migration and invasion assays. For the confirmed that 3-UTR of CCR7 is a direct target of Let-7a by employing luciferase assay for the reporter gene expressing Let-7a binding sites of CCR7 3-UTR. We also established in vivo invasion animal model using transparent zebrafish embryos to detect the effect of Let-7a on in vivo system.
Results
First, we determined the over-expression of CCR7 in both and higher expression of CCL21 in malignant tissues than in their normal counterparts in breast cancer patients. We also detected the reverse-correlation in expression of CCR7 and Let-7a in breast cancer cell lines and breast cancer patient tissues. Synthetic Let-7a decreased breast cancer cell proliferation, migration and invasion as well as CCR7 protein expression in MDA-MB 231 cells. Inhibitor of Let-7a reversed these Let-7a effects on breast cancer cells in MCF-7 cells. It was confirmed that 3-UTR of CCR7 is a direct target of Let-7a by employing luciferase assay for the reporter gene expressing Let-7a binding sites of CCR7 3-UTR. Interestingly, we analyzed the in vivo invasion, which MDA-MB231 cells after synthetic Let-7a oligo-nucleotides transfection could not invade into the vessels in zebrafish embryos.
Conclusions
These results suggest that targeting of CCL21-CCR7 signaling is a valid approach for breast cancer therapy and Let-7a directly binds the 3-UTR of CCR7 and blocks its protein expression, thereby suppressing migration and invasion of human breast cancer cells. Furthermore, this study underscores the therapeutic potential of Let-7a as an anti-tumor and anti-metastatic manager in breast cancer patients.