High-grade serous ovarian carcinoma (HGSOC) accounts for the highest number of deaths among patients with epithelial ovarian cancer. However, the molecular mechanisms underlying HGSOC tumorigenesis are currently unclear. In the present study, a lentiviral expression system was employed to manipulate forkhead box D1 (FOXD1) expression in ovarian cancer cells. Immunohistochemical staining was used to examine the expression of FOXD1 in tissue samples. Clonogenic and MTT assays were employed to evaluate cell proliferation, and flow cytometry was applied for cell cycle analysis. Dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine the role of FOXD1 in regulating p21 expression. The results demonstrated that FOXD1 expression was downregulated in HGSOC, and high expression levels of FOXD1 were found to be a predictor of good prognosis. FOXD1 significantly inhibited the proliferation of human ovarian cancer cells and induced cell cycle arrest at G1 phase in vitro. In addition, exogenous FOXD1 expression inhibited ovarian cancer cell growth in vivo. Furthermore, microRNA (miR)-30a-5p and miR-200a-5p were observed to be upregulated in HGSOC, and function as direct negative regulators of FOXD1 by targeting its 3'-untranslated region. The present study also revealed that FOXD1 promotes p21 expression in a p53-independent manner. In conclusion, the results of the present study indicate a direct association between FOXD1 and p21 that may be mediated by miR-30a-5p and miR-200a-5p. The authors hypothesize that FOXD1 may serve as a biomarker or therapeutic target in HGSOC.
Activation of the FOXM1 signaling pathway and the PI3K/AKT/mTOR signaling pathway is associated with poor prognosis in ovarian cancer. In this study, we demonstrated that P15 (KIAA0101) was significantly upregulated in high-grade serous ovarian cancer (HGSOC) and that high KIAA0101 expression was associated with poor prognosis. FOXM1 transcriptionally activated KIAA0101 to drive proliferation and metastasis of ovarian cancer cells. KIAA0101 activated the PI3K/AKT/mTOR signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in ovarian cancer cells resulting in cisplatin resistance. Thus, KIAA0101 was closely related to the FOXM1 and PI3K/AKT/mTOR signaling pathways. Collectively, these findings provide insights into the mechanisms of poor prognosis of ovarian cancer and have implications for the development of both predictive and therapeutic biomarkers for the treatment of ovarian cancer.
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