EGF decreases the abundance of microRNAs that restrain oncogenic transcription factors.
Epidermal growth factor (EGF) stimulates cells by launching gene expression programs that are frequently deregulated in cancer. MicroRNAs, which attenuate gene expression by binding complementary regions in messenger RNAs, are broadly implicated in cancer. Using genome-wide approaches, we showed that EGF stimulation initiates a coordinated transcriptional program of microRNAs and transcription factors. The earliest event involved a decrease in the abundance of a subset of 23 microRNAs. This step permitted rapid induction of oncogenic transcription factors, such as c-FOS, encoded by immediate early genes. In line with roles as suppressors of EGF receptor (EGFR) signaling, we report that the abundance of this early subset of microRNAs is decreased in breast and in brain tumors driven by the EGFR or the closely related HER2. These findings identify specific microRNAs as attenuators of growth factor signaling and oncogenesis.
Avraham
Roi
R
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Sas-Chen
Aldema
A
Manor
Ohad
O
Steinfeld
Israel
I
Shalgi
Reut
R
Tarcic
Gabi
G
Bossel
Noa
N
Zeisel
Amit
A
Amit
Ido
I
Zwang
Yaara
Y
Enerly
Espen
E
Russnes
Hege G
HG
Biagioni
Francesca
F
Mottolese
Marcella
M
Strano
Sabrina
S
Blandino
Giovanni
G
Børresen-Dale
Anne-Lise
AL
Pilpel
Yitzhak
Y
Yakhini
Zohar
Z
Segal
Eran
E
Yarden
Yosef
Y
D001932:Brain Neoplasms / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects
D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; D012334:RNA, Neoplasm; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors