Nuclear receptor coactivator 6 promotes HTR-8/SVneo cell invasion and migration by activating NF-κB-mediated MMP9 transcription

Objectives: NCOA6 is a transcription coactivator; its deletion in mice results in growth retardation and lethality between 8.5 and 12.5 dpc with defects in the placenta. However, the transcription factor(s) and the mechanism(s) involved in the function of NCOA6 in placentation have not been elucidated. Here, the roles of NCOA6 in human cytotrophoblast invasion and migration were studied. Materials and Methods: Human placenta tissues were collected from normal pregnancies and pregnancies complicated by early-onset severe preeclampsia (sPE). Immunofluorescence, RT-qPCR and Western blotting were used to determine NCOA6 expression. Transwell invasion/migration assays were performed to explore whether NCOA6 knockdown affected human placenta-derived HTR-8/SVneo cell invasion/migration. Gelatin zymography was performed to examine the change in the gelatinolytic activities of secreted MMP2 and MMP9. Luciferase reporter assays were used to explore whether NCOA6 coactivated NF-kappa B-mediated MMP9 transcription. Results: NCOA6 is mainly expressed in the human placental trophoblast column, as well as in the EVTs. HTR-8/SVneo cell invasion and migration were significantly attenuated after NCOA6 knockdown, and the secretion of MMP9 was decreased due to transcriptional suppression. NCOA6 was further found to coactivate NF-kappa B-mediated MMP9 transcription. Moreover, expression of NCOA6 was impaired in placentas of patients complicated by early-onset sPE. Conclusions: Thus, we demonstrated that NCOA6 is important for cytotrophoblast invasion/migration, at least partially, by activating NF-kappa B-mediated MMP9 transcription; the downregulation of NCOA6 may contribute to the pathogenesis of early-onset sPE.