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Cell Rep. 2019 Dec 24;29(13):4389-4406.e10. doi: 10.1016/j.celrep.2019.11.085.

miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer.

Author information

1
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
2
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
3
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
5
Division of Medicine, Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway.
6
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
7
Department of Gynecology and Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
8
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
9
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
10
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
11
Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
12
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Division of Medicine, Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway.
13
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
14
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: pchaluvally@mcw.edu.

Abstract

Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC). Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription. As a consequence, miR551b upregulates the expression of oncostatin M receptor (OSMR) and interleukin-31 receptor-α (IL-31RA) as well as their ligands OSM and IL-31 through STAT3 transcription. We defined this set of genes induced by miR551b-3p as the "oncostatin signaling module," which provides oncogenic addictions in cancer cells. Notably, OSM is highly expressed in TNBC, and the elevated expression of OSM associates with poor outcome in estrogen-receptor-negative breast cancer patients. Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of the OSM signaling module and reduced tumor growth, as well as migration and invasion of breast cancer cells.

KEYWORDS:

IPO8; OSMR; RNAi; STAT3; miR551b; miRNA-therapy; oncostatin

PMID:
31875548
DOI:
10.1016/j.celrep.2019.11.085
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