Regulation of non-AU-rich element containing c-fms proto-oncogene expression by HuR in breast cancer.
The role of RNA-binding proteins in cancer biology is recognized increasingly. The nucleocytoplasmic shuttling and AU-rich RNA-binding protein HuR stabilizes several cancer-related target mRNAs. The proto-oncogene c-fms, whose 3'untranslated region (3'UTR) is not AU-rich, is associated with poor prognosis in breast cancer. Using a large breast-cancer tissue array (N=670), we found nuclear HuR expression to be associated with nodal metastasis and independently with poor survival (P=0.03, RR 1.45), as well as to be co-expressed with c-fms in the breast tumors (P=0.0007). We described c-fms mRNA as a direct target of HuR in vivo, and that HuR bound specifically to a 69-nt region containing 'CUU' motifs in 3'UTR c-fms RNA. Overexpressing or silencing HuR significantly up- or down-regulated c-fms RNA expression, respectively. We also found that known glucocorticoid stimulation of c-fms RNA and protein is largely dependent on the presence of HuR. HuR, by binding to the 69-nt wild type, but not mutant, c-fms sequence can regulate reporter gene expression post-transcriptionally. We are the first to describe that HuR can regulate gene expression by binding non-AU-rich sequences in 3'UTR c-fms RNA. Collectively, our findings suggest that HuR plays a supportive role for c-fms in breast cancer progression by binding a 69-nt element in its 3'UTR, thus regulating its expression.
Woo
H-H
HH
Arizona Cancer Center, University of Arizona, Tucson, AZ 85724-5024, USA.
Zhou
Y
Y
Yi
X
X
David
C L
CL
Zheng
W
W
Gilmore-Hebert
M
M
Kluger
H M
HM
Ulukus
E C
EC
Baker
T
T
Stoffer
J B
JB
Chambers
S K
SK
D020413:3' Untranslated Regions; D000954:Antigens, Surface / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D015536:Down-Regulation; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016236:Genes, fms; D006801:Humans; D007150:Immunohistochemistry; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000502:physiology*; D016019:Survival Analysis
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016601:RNA-Binding Proteins