miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.
MicroRNAs (miRNAs) are involved in tumorigenecity by regulating specific oncogenes and tumor suppressor genes, and their roles in breast cancer stem cells (BCSCs) are becoming apparent. Distinct from the CD44(+)/CD24(-/low) sub-population, we have isolated a novel PROCR(+)/ESA(+) BCSC sub-population. To explore miRNA-regulatory mechanisms in this sub-population, we performed miRNA expression profiling and found miR-495 as the most highly upegulated miRNA in PROCR(+)/ESA(+) cells. Coincidently, high upregulation of miR-495 was also found in CD44(+)/CD24(-/low) BCSCs, reflecting its potential importance in maintaining common BCSC properties. Ectopic expression of miR-495 in breast cancer cells promoted their colony formation in vitro and tumorigenesis in mice. miR-495 directly suppressed E-cadherin expression to promote cell invasion and inhibited REDD1 expression to enhance cell proliferation in hypoxia through post-transcriptional mechanism. miR-495 expression was directly modulated by transcription factor E12/E47, which itself is highly expressed in BCSCs. These findings reveal a novel regulatory pathway centered on miR-495 that contributes to BCSC properties and hypoxia resistance.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
W W
WW
Hwang-Verslues
P-H
PH
Chang
P-C
PC
Wei
C-Y
CY
Yang
C-K
CK
Huang
W-H
WH
Kuo
J-Y
JY
Shew
K-J
KJ
Chang
E Y-H P
EY
Lee
W-H
WH
Lee
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058127:Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
D015820:Cadherins; C469991:DDIT4 protein, human; C559640:MIRN497 microRNA, human; D035683:MicroRNAs; D058127:Transcription Factor 3; D014157:Transcription Factors