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PMID: 25659578 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-α.

Oncogene ·Vol. 34 ·No. 37 ·2015-09-10 ·Pages 4890-900

Xing F, Sharma S, Liu Y, Mo YY, Wu K, Zhang YY, Pochampally R, Martinez LA, Lo HW, Watabe K

Abstract

The median survival time of breast cancer patients with brain metastasis is less than 6 months, and even a small metastatic lesion often causes severe neurological disabilities. Because of the location of metastatic lesions, a surgical approach is limited and most chemotherapeutic drugs are ineffective owing to the blood brain barrier (BBB). Despite this clinical importance, the molecular basis of the brain metastasis is poorly understood. In this study, we have isolated RNA from samples obtained from primary breast tumors and also from brain metastatic lesions followed by microRNA profiling analysis. Our results revealed that the miR-509 is highly expressed in the primary tumors, whereas the expression of this microRNA is significantly decreased in the brain metastatic lesions. MicroRNA target prediction and the analysis of cytokine array for the cells ectopically expressed with miR-509 demonstrated that this microRNA was capable of modulating the two genes essential for brain invasion, RhoC and TNF-α that affect the invasion of cancer cells and permeability of BBB, respectively. Importantly, high levels of TNF-α and RhoC-induced MMP9 were significantly correlated with brain metastasis-free survival of breast cancer patients. Furthermore, the results of our in vivo experiments indicate that miR-509 significantly suppressed the ability of cancer cells to metastasize to the brain. These findings suggest that miR-509 has a critical role in brain metastasis of breast cancer by modulating the RhoC-TNF-α network and that this miR-509 axis may represent a potential therapeutic target or serve as a prognostic tool for brain metastasis.

MeSH Terms
Animals Blood-Brain Barrier/metabolism,pathology Brain Neoplasms/genetics,secondary Breast Neoplasms/genetics,pathology Cells, Cultured Female Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor HEK293 Cells Humans MCF-7 Cells Mice Mice, Nude MicroRNAs/genetics,physiology Tumor Necrosis Factor-alpha/genetics rho GTP-Binding Proteins/genetics rhoC GTP-Binding Protein
Chemicals
MIRN509 microRNA, human MicroRNAs Tumor Necrosis Factor-alpha RHOC protein, human rho GTP-Binding Proteins rhoC GTP-Binding Protein
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Xing F
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Sharma S
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Liu Y
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Mo Y-Y
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Wu K
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Zhang Y-Y
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Pochampally R
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Martinez L A
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Lo H-W
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Watabe K
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2014.412
Published
2015-09-10
Epub
2015-00-09
Pages
4890-900
Language
English
Region
England
NLM ID
8711562
PMCID
PMC4530094
Subset
IM
Grants
NCI NIH HHS · R01CA129000 · United States
NCI NIH HHS · R01CA173499 · United States
NCI NIH HHS · R01 CA154989 · United States
NCI NIH HHS · R01 CA124650 · United States
NCI NIH HHS · R01CA124650 · United States
NCI NIH HHS · R01 CA173499 · United States
NINDS NIH HHS · R01 NS087169 · United States
NCI NIH HHS · P30 CA012197 · United States
NCI NIH HHS · R01 CA129000 · United States
NCI NIH HHS · R01 CA151851 · United States
External Links
PubMed source DOI: 10.1038/onc.2014.412 PMC Full Text View journal details
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