TY - JOUR
T1 - Integrin α5 down-regulation by miR-205 suppresses triple negative breast cancer stemness and metastasis by inhibiting the Src/Vav2/Rac1 pathway
AU - Xiao, Yajuan
AU - Li, Yunfei
AU - Tao, Hua
AU - Humphries, Brock
AU - Li, Aimin
AU - Jiang, Yiguo
AU - Yang, Chengfeng
AU - Luo, Rongcheng
AU - Wang, Zhishan
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Triple negative breast cancer (TNBC) usually displays more aggressive metastasis, the underlying mechanism is unclear. Previous studies showed that microRNA-205 (miR-205) has controversial roles in cancer, however, its role in TNBC metastasis and the underlying mechanism have not been well-understood. In this study we found that miR-205 expression level is extremely low in basal mesenchymal-like highly migratory and invasive TNBC cells. Stably re-expressing miR-205 in TNBC cells significantly reduced their migration, invasion capability and cancer stem cell (CSC)-like property. Nude mouse orthotopic mammary xenograft tumor model study revealed that miR-205 re-expression greatly decreases TNBC tumor growth and abolishes spontaneous lung metastasis. Mechanistic studies demonstrated that miR-205 inhibits TNBC cell metastatic traits and tumor metastasis by down-regulating integrin α5 (ITGA5). Moreover, ITGA5 knockout using the CRISPR/Cas9 technique achieved the same strong inhibitory effect on TNBC cell CSC-like property and tumor metastasis as re-expressing miR-205 did. Further mechanistic studies indicated that ITGA5 down-regulation by miR-205 re-expression impairs TNBC cell metastatic traits by inhibiting the Src/Vav2/Rac1 pathway. Together, our findings suggest that miR-205 and ITGA5 may serve as potential targets for developing effective therapies for metastatic TNBC.
AB - Triple negative breast cancer (TNBC) usually displays more aggressive metastasis, the underlying mechanism is unclear. Previous studies showed that microRNA-205 (miR-205) has controversial roles in cancer, however, its role in TNBC metastasis and the underlying mechanism have not been well-understood. In this study we found that miR-205 expression level is extremely low in basal mesenchymal-like highly migratory and invasive TNBC cells. Stably re-expressing miR-205 in TNBC cells significantly reduced their migration, invasion capability and cancer stem cell (CSC)-like property. Nude mouse orthotopic mammary xenograft tumor model study revealed that miR-205 re-expression greatly decreases TNBC tumor growth and abolishes spontaneous lung metastasis. Mechanistic studies demonstrated that miR-205 inhibits TNBC cell metastatic traits and tumor metastasis by down-regulating integrin α5 (ITGA5). Moreover, ITGA5 knockout using the CRISPR/Cas9 technique achieved the same strong inhibitory effect on TNBC cell CSC-like property and tumor metastasis as re-expressing miR-205 did. Further mechanistic studies indicated that ITGA5 down-regulation by miR-205 re-expression impairs TNBC cell metastatic traits by inhibiting the Src/Vav2/Rac1 pathway. Together, our findings suggest that miR-205 and ITGA5 may serve as potential targets for developing effective therapies for metastatic TNBC.
KW - Cancer stem cell (CSC)-Like property
KW - Integrin α5 (ITGA5)
KW - Metastatic triple negative breast cancer (TNBC)
KW - Rho GTPase Rac1
KW - microRNA-205 (miR-205)
UR - http://www.scopus.com/inward/record.url?scp=85049912523&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049912523&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2018.06.037
DO - 10.1016/j.canlet.2018.06.037
M3 - Article
C2 - 29964204
AN - SCOPUS:85049912523
SN - 0304-3835
VL - 433
SP - 199
EP - 209
JO - Cancer Letters
JF - Cancer Letters
ER -