Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis.
Expression profiling has identified metastasis-associated microRNAs (miRNA) but technical limitations hinder the discovery of metastasis-suppressing miRNAs. In this study, we sought metastasis-suppressing miRNAs by functional screening. Individual miRNAs were lentivirally introduced into metastatic MDA-MB-231 breast cancer cells and analyzed for effects on cell migration, a critical step in cancer metastasis. Among 486 miRNAs screened, 14 were identified that included all of the members of the miRNA-196 family (miR-196a1, miR-196a2, and miR-196b). Enforced expression of miR-196a1/2 or miR-196b abrogated in vitro invasion and in vivo spontaneous metastasis of breast cancer cells, indicating that members of the miR-196 family are potent metastasis suppressors. We found that miR-196 inhibited the expression of transcription factor HOXC8. Functional linkage was implied by small interfering RNA-mediated knockdown of HOXC8, which suppressed cell migration and metastasis, and by ectopic expression of HOXC8, which prevented the effects of miR-196 on cell migration and metastasis. Unlike other metastasis-associated miRNAs that have been described, the expressions of miR-196 were not correlated with breast cancer cell migration or the metastatic status of clinical breast tumor specimens. Instead, we detected an excellent correlation between the ratio of miR-196 to HOXC8 messages and the migratory behavior of breast cancer cell lines as well as the metastatic status of clinical samples. Our findings identify miRNA-196s as potent metastasis suppressors and reveal that the ratio of miR-196s to HOXC8 mRNA might be an indicator of the metastatic capability of breast tumors.
Li
Yong
Y
Departments of Biochemistry and Molecular Biology, Cellular Biology and Anatomy, and Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.
Zhang
Maoxiang
M
Chen
Huijun
H
Dong
Zheng
Z
Ganapathy
Vadivel
V
Thangaraju
Muthusamy
M
Huang
Shuang
S
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D017931:DNA Primers; D005260:Female; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000235:genetics*
D017931:DNA Primers; C489815:HOXC8 protein, human; D018398:Homeodomain Proteins; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger