MicroRNAs 206 and 21 cooperate to promote RAS-extracellular signal-regulated kinase signaling by suppressing the translation of RASA1 and SPRED1.

Autor:	Sharma SB; Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA Program in Cancer Cell Biology, West Virginia University, Morgantown, West Virginia, USA., Lin CC; Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA., Farrugia MK; Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA Program in Cancer Cell Biology, West Virginia University, Morgantown, West Virginia, USA., McLaughlin SL; The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA., Ellis EJ; The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA., Brundage KM; The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA., Salkeni MA; The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA Department of Medicine, West Virginia University, Morgantown, West Virginia, USA., Ruppert JM; Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA mruppert@hsc.wvu.edu.
Jazyk:	angličtina
Zdroj:	Molecular and cellular biology [Mol Cell Biol] 2014 Nov 15; Vol. 34 (22), pp. 4143-64. Date of Electronic Publication: 2014 Sep 08.
DOI:	10.1128/MCB.00480-14
Abstrakt:	Despite the low prevalence of activating point mutation of RAS or RAF genes, the RAS-extracellular signal-regulated kinase (ERK) pathway is implicated in breast cancer pathogenesis. Indeed, in triple-negative breast cancer (TNBC), there is recurrent genetic alteration of pathway components. Using short hairpin RNA (shRNA) methods, we observed that the zinc finger transcription factor Krüppel-like factor 4 (KLF4) can promote RAS-ERK signaling in TNBC cells. Endogenous KLF4 bound to the promoter regions and promoted the expression of two microRNAs (miRs), miR-206 and miR-21 (i.e., miR-206/21). Antisense-mediated knockdown (anti-miR) revealed that miR-206/21 coordinately promote RAS-ERK signaling and the corresponding cell phenotypes by inhibiting translation of the pathway suppressors RASA1 and SPRED1. In TNBC cells, including cells with mutation of RAS, the suppression of either RASA1 or SPRED1 increased the levels of GTP-bound, wild-type RAS and activated ERK 1/2. Unlike the control cells, treatment of RASA1- or SPRED1-suppressed cells with anti-miR-206/21 had little or no impact on the level of activated ERK 1/2 or on cell proliferation and failed to suppress tumor initiation. These results identify RASA1 and SPRED1 mRNAs as latent RAS-ERK pathway suppressors that can be upregulated in tumor cells by anti-miR treatment. Consequently, KLF4-regulated miRs are important for the maintenance of RAS-ERK pathway activity in TNBC cells. (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
Databáze:	MEDLINE
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