ABSTRACT
High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs. HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.
Subject(s)
Adaptor Proteins, Signal Transducing , Cell Transformation, Neoplastic , Epithelial Cells , Fallopian Tubes , Transcription Factors , YAP-Signaling Proteins , Humans , Female , YAP-Signaling Proteins/metabolism , Epithelial Cells/virology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Cell Transformation, Neoplastic/genetics , Fallopian Tubes/pathology , Fallopian Tubes/virology , Fallopian Tubes/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Papillomaviridae/genetics , Cell Proliferation , Animals , Papillomavirus Infections/virology , Papillomavirus Infections/pathology , Papillomavirus Infections/genetics , Papillomavirus Infections/complications , Ovarian Neoplasms/pathology , Ovarian Neoplasms/virology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Mice , Immunity, InnateABSTRACT
Current models of bereavement care do not address all of bereaved parents' unique needs. Diverse challenges limit parents' ability to access certain bereavement services. A web-based intervention prototype for bereaved parents was developed. Using convenience and snowball techniques, 14 participants (pediatric providers, software developers, and bereaved parents) were enrolled in a descriptive, cross-sectional feasibility and usability study. While the intervention was generally considered acceptable, three themes were identified to enhance its usability and acceptability: timing; delivery; and revisions. Further intervention development is needed to improve both short- and long-term physical and psychological outcomes for bereaved parents.