title: 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.
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.
authors.affiliation: Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus , Aurora, CO 80045 , USA.
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Avasarala
authors.forename: Michelle
authors.initials: M
authors.lastname: Van Scoyk
authors.forename: Jianbin
authors.initials: J
authors.lastname: Wang
authors.forename: Marybeth
authors.initials: M
authors.lastname: Sechler
authors.forename: Katherine
authors.initials: K
authors.lastname: Vandervest
authors.forename: Christine
authors.initials: C
authors.lastname: Brzezinski
authors.forename: Colin
authors.initials: C
authors.lastname: Weekes
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.forename: John
authors.initials: J
authors.lastname: Arcaroli
authors.forename: Richard E
authors.initials: RE
authors.lastname: Davis
authors.forename: Rama Kamesh
authors.initials: RK
authors.lastname: Bikkavilli
authors.forename: Robert A
authors.initials: RA
authors.lastname: Winn
keywords: Frizzled 9; MDM2; Non-small cell lung cancer; Wnt7a; hsa-miR29b; p53