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
Affiliations
Deepak Parashar
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Anjali Geethadevi
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Miriam Ragle Aure
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
Jyotsna Mishra
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Jasmine George
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Changliang Chen
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Manoj K. Mishra
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Andliena Tahiri
Division of Medicine, Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
Wei Zhao
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Bindu Nair
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Yiling Lu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Lingegowda S. Mangala
Department of Gynecology and Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Cristian Rodriguez-Aguayo
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Gabriel Lopez-Berestein
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Amadou K.S. Camara
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Mingyu Liang
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Janet S. Rader
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
Ramani Ramchandran
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
Ming You
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
Anil K. Sood
Department of Gynecology and Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Vessela N. Kristensen
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
Gordon B. Mills
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Sunila Pradeep
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
Pradeep Chaluvally-Raghavan
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; Corresponding author
Summary: 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. : Parashar et al. demonstrate that the mature microRNA-551b-3p translocates to the nucleus for transcriptional activation of STAT3 gene. As a consequence, miR551b activates an autocrine signaling loop through the upregulation of oncostatin family genes, including oncostatin, and its receptors for the growth and metastasis of triple-negative breast cancer. Keywords: miR551b, oncostatin, STAT3, OSMR, miRNA-therapy, IPO8, RNAi
