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
Sreedevi Avasarala,
Michelle Van Scoyk,
Jianbin Wang,
Marybeth Sechler,
Katherine Vandervest,
Christine Brzezinski,
Colin Weekes,
Michael G. Edwards,
John Arcaroli,
Richard E. Davis,
Rama Kamesh Bikkavilli,
Robert A. Winn
Affiliations
Sreedevi Avasarala
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Michelle Van Scoyk
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Jianbin Wang
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO 80045, USA
Marybeth Sechler
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Katherine Vandervest
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Christine Brzezinski
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Colin Weekes
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Michael G. Edwards
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
John Arcaroli
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Richard E. Davis
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO 80045, USA
Rama Kamesh Bikkavilli
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Robert A. Winn
Division of Pulmonary and Critical Care Sciences, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Summary 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.
