Universität zu Köln

Langsch, Stephanie, Baumgartner, Ulrich ORCID: 0000-0001-8170-0567, Haemmig, Stefan ORCID: 0000-0001-5014-4393, Schlup, Cornelia, Schafer, Stephan C., Berezowska, Sabina ORCID: 0000-0001-5442-9791, Rieger, Gregor, Dorn, Patrick, Tschan, Mario P. ORCID: 0000-0001-5897-3647 and Vassella, Erik (2016). miR-29b Mediates NF-kappa B Signaling in KRAS-Induced Non-Small Cell Lung Cancers. Cancer Res., 76 (14). S. 4160 - 4170. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

A global understanding of miRNA function in EGFR signaling pathways may provide insights into improving the management of KRAS-mutant lung cancers, which remain relatively recalcitrant to treatment. To identify miRNAs implicated in EGFR signaling, we transduced bronchial epithelial BEAS-2B cells with retroviral vectors expressing KRAS(G12V) and monitored miRNA expression patterns by microarray analysis. Through this approach, we defined miR-29b as an important target for upregulation by mutant KRAS in non-small cell lung cancers. Cell biologic analyses showed that pharmacologic inhibition of EGFR or MEK was sufficient to reduce levels of miR-29b, while PI3K inhibition had no effect. In KRAS(G12V)-transduced BEAS-2B cells, introduction of anti-miR-29b constructs increased the sensitivity to apoptosis, arguing that miR-29b-mediated apoptotic resistance conferred by mutant KRAS. Mechanistic investigations traced this effect to the ability of miR-29b to target TNFAIP3/A20, a negative regulator of NF-kappa B signaling. Accordingly, overexpression of an miR-29b-refractory isoform of TNFAIP3 restored NF-kappa B and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b. We also noted that miR-29b could confer sensitivity to intrinsic apoptosis triggered by exposure to cisplatin, a drug used widely in lung cancer treatment. Thus, miR-29b expression may tilt cells from extrinsic to intrinsic mechanisms of apoptosis. Overall, our results reveal a complexity in cancer for miR-29b, which can act as either an oncogene or tumor suppressor gene depending on signaling context. (C)2016 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Langsch, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumgartner, Ulrich UNSPECIFIED orcid.org/0000-0001-8170-0567 UNSPECIFIED Haemmig, Stefan UNSPECIFIED orcid.org/0000-0001-5014-4393 UNSPECIFIED Schlup, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schafer, Stephan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berezowska, Sabina UNSPECIFIED orcid.org/0000-0001-5442-9791 UNSPECIFIED Rieger, Gregor UNSPECIFIED UNSPECIFIED UNSPECIFIED Dorn, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Tschan, Mario P. UNSPECIFIED orcid.org/0000-0001-5897-3647 UNSPECIFIED Vassella, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-269835
DOI:	10.1158/0008-5472.CAN-15-2580
Journal or Publication Title:	Cancer Res.
Volume:	76
Number:	14
Page Range:	S. 4160 - 4170
Date:	2016
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACUTE MYELOID-LEUKEMIA; TUMOR-SUPPRESSOR GENE; GRANULOCYTIC DIFFERENTIATION; ONCOGENIC RAS; APOPTOSIS; ADENOCARCINOMA; RESISTANCE; GEFITINIB; TRANSFORMATION; ACTIVATION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26983