Regulation of non-AU-rich element containing c-fms proto-oncogene expression by HuR in breast cancer

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Woo H., Zhou Y., Yi X., David C. L., Zheng W., Gilmore-Hebert M., ...Daha Fazla

ONCOGENE, cilt.28, sa.9, ss.1176-1186, 2009 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 28 Sayı: 9
  • Basım Tarihi: 2009
  • Doi Numarası: 10.1038/onc.2008.469
  • Dergi Adı: ONCOGENE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1176-1186
  • Anahtar Kelimeler: breast cancer, c-fms proto-oncogene, post-transcriptional regulation, HuR, MESSENGER-RNA STABILITY, STIMULATING FACTOR-1 RECEPTOR, CSF-1 RECEPTOR, BINDING PROTEIN, POSTTRANSCRIPTIONAL REGULATION, CYCLOOXYGENASE-2 EXPRESSION, MONOCYTIC DIFFERENTIATION, QUANTITATIVE-ANALYSIS, CROSS-LINKING, CARCINOMA
  • Dokuz Eylül Üniversitesi Adresli: Evet

Özet

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.