NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells
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Ki-Hyung Kim1,2,3,*, Seong-Hwan Park1,5,*, Kee Hun Do1,5,*, Juil Kim1,5, Kyung Un Choi2,4, Yuseok Moon1,2,5
1Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea
2Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea
3Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Busan, South Korea
4Department of Pathology, Pusan National University School of Medicine, Busan, South Korea
5Research Institute for Basic Sciences, Pusan National University, Busan, South Korea
*Ki-Hyung Kim, Kee Hun Do and Seong-Hwan Park equally contributed to the present study
Yuseok Moon, email: [email protected]
Keywords: NAG-1, epithelial ovary cancer, paclitaxel, NF-κB, chemoresistance
Received: February 24, 2016 Accepted: September 20, 2016 Published: September 30, 2016
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFβ-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.
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