The ascites that develops in advanced OC, both at diagnosis and upon recurrence, is a rich source of multicellular spheroids/aggregates (MCSs/MCAs), which are the major seeds of tumor cell dissemination within the abdominal cavity. However, the molecular mechanism by which specific ascites-derived tumor cells survive and metastasize remains largely unknown. In this study, we elucidated cancer stem cell (CSC) properties of ascites-derived MCSs, concomitant with enhanced malignancy, induced EMT, and low KLF9 (Krüppel-like factor 9) expression, compared with PTCs. KLF9 was also downregulated in OC cell line-derived spheroids and the CD117+ CD44+ subpopulation in MCSs. Functional experiments demonstrated that KLF9 negatively modulated stem-like properties in OC cells. Mechanistic studies revealed that KLF9 reduced the transcriptional expression of Notch1 by directly binding to the Notch1 promoter, thereby inhibiting the function of slug in a CSL-dependent manner. Clinically, expression of KLF9 was associated with histological grade and loss of KLF9 predicts poor prognosis in OC.
Keywords: KLF9; Notch1; multicellular spheroids; ovarian cancer stem cells; slug.
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.