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

Deepak Parashar; Anjali Geethadevi; Miriam Ragle Aure; Jyotsna Mishra; Jasmine George; Changliang Chen; Manoj K Mishra; Andliena Tahiri; Wei Zhao; Bindu Nair; Yiling Lu; Lingegowda S Mangala; Cristian Rodriguez-Aguayo; Gabriel Lopez-Berestein; Amadou K S Camara; Mingyu Liang; Janet S Rader; Ramani Ramchandran; Ming You; Anil K Sood; Vessela N Kristensen; Gordon B Mills; Sunila Pradeep; Pradeep Chaluvally-Raghavan

doi:10.1016/j.celrep.2019.11.085

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

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

Authors

Deepak Parashar¹, Anjali Geethadevi¹, Miriam Ragle Aure², Jyotsna Mishra³, Jasmine George¹, Changliang Chen¹, Manoj K Mishra⁴, Andliena Tahiri⁵, Wei Zhao⁶, Bindu Nair¹, Yiling Lu⁶, Lingegowda S Mangala⁷, Cristian Rodriguez-Aguayo⁸, Gabriel Lopez-Berestein⁸, Amadou K S Camara³, Mingyu Liang⁴, Janet S Rader⁹, Ramani Ramchandran¹⁰, Ming You¹¹, Anil K Sood⁷, Vessela N Kristensen¹², Gordon B Mills⁶, Sunila Pradeep¹³, Pradeep Chaluvally-Raghavan¹⁴

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Nucleus / metabolism
Cell Proliferation / genetics
Disease Progression*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Molecular Targeted Therapy
Neoplasm Invasiveness
Oncostatin M / metabolism*
STAT3 Transcription Factor / metabolism
Signal Transduction*
Transcription, Genetic
Transcriptional Activation / genetics
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / pathology*
Up-Regulation / genetics
beta Karyopherins / metabolism

Substances

IPO8 protein, human
MIRN551B microRNA, human
MicroRNAs
STAT3 Transcription Factor
STAT3 protein, human
beta Karyopherins
Oncostatin M

Abstract

Publication types

MeSH terms

Substances

Grants and funding