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Biol Open. 2013 May 22;2(7):675-85. doi: 10.1242/bio.20134507. Print 2013 Jul 15.

hsa-miR29b, a critical downstream target of non-canonical Wnt signaling, plays an anti-proliferative role in non-small cell lung cancer cells via targeting MDM2 expression.

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1
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus , Aurora, CO 80045 , USA.

Abstract

In non-small cell lung cancer cell lines, activation of β-catenin independent signaling, via Wnt7a/Frizzled9 signaling, leads to reversal of cellular transformation, reduced anchorage-independent growth and induction of epithelial differentiation. miRNA expression profiling on a human lung adenocarcinoma cell line (A549) identified hsa-miR29b as an important downstream target of Wnt7a/Frizzled9 signaling. We show herein that hsa-miR29b expression is lost in non-small cell lung cancer (NSCLC) cell lines and stimulation of β-catenin independent signaling, via Wnt7a expression, in NSCLC cell lines results in increased expression of hsa-miR29b. Surprisingly, we also identify specific regulation of hsa-miR29b by Wnt7a but not by Wnt3, a ligand for β-catenin-dependent signaling. Interestingly, knockdown of hsa-miR29b was enough to abrogate the tumor suppressive effects of Wnt7a/Frizzled9 signaling in NSCLC cells, suggesting that hsa-miR29b is an important mediator of β-catenin independent signaling. Finally, we show for the first time that hsa-miR29b plays an important role as a tumor suppressor in lung cancer by targeting murine double mutant 2 (MDM2), revealing novel nodes for Wnt7a/Frizzled9-mediated regulation of NSCLC cell proliferation.

KEYWORDS:

Frizzled 9; MDM2; Non-small cell lung cancer; Wnt7a; hsa-miR29b; p53

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