title: NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.|Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea.|Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Busan, South Korea.
authors.forename: Ki-Hyung
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.|Research Institute for Basic Sciences, Pusan National University, Busan, South Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.|Research Institute for Basic Sciences, Pusan National University, Busan, South Korea.
authors.forename: Kee Hun
authors.initials: KH
authors.lastname: Do
authors.affiliation: Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.|Research Institute for Basic Sciences, Pusan National University, Busan, South Korea.
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea.|Department of Pathology, Pusan National University School of Medicine, Busan, South Korea.
authors.forename: Kyung Un
authors.initials: KU
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.|Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea.|Research Institute for Basic Sciences, Pusan National University, Busan, South Korea.
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000473:pathology*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D053208:Kaplan-Meier Estimate; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D018613:Microscopy, Confocal; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D010053:Ovary / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D018925:Chemokines; D066246:ErbB Receptors; D055436:Growth Differentiation Factor 15; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017239:Paclitaxel; D051901:Smad4 Protein; D013467:Sulindac; D000099151:MAP Kinase Kinase Kinase 7; C526140:GDF15 protein, human; C507779:MYD88 protein, human; C497796:SMAD4 protein, human; C025462:sulindac sulfide; C512478:EGFR protein, human
keywords: NAG-1; NF-κB; chemoresistance; epithelial ovary cancer; paclitaxel