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ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA
- Source :
- Cancer research. 77(15)
- Publication Year :
- 2016
-
Abstract
- Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARHGAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR-200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess. Cancer Res; 77(15); 4051–64. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
RHOA
Blotting, Western
Down-Regulation
Fluorescent Antibody Technique
Triple Negative Breast Neoplasms
Real-Time Polymerase Chain Reaction
Metastasis
Focal adhesion
03 medical and health sciences
Mice
Downregulation and upregulation
Cell Movement
Cell Line, Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Triple-negative breast cancer
biology
GTPase-Activating Proteins
Cancer
Cell migration
medicine.disease
Cell biology
Enzyme Activation
Gene Expression Regulation, Neoplastic
MicroRNAs
030104 developmental biology
Oncology
Cancer cell
biology.protein
Heterografts
Female
rhoA GTP-Binding Protein
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 77
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....1d46021ce8795fa2178f7dfa80e2e9c5