Aberrant Activation of ERK/FOXM1 Signaling Cascade Triggers the Cell Migration/Invasion in Ovarian Cancer Cells

Abstract

Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor essential for cell cycle progression. Numerous studies have documented that FOXM1 has multiple functions in tumorigenesis and its elevated levels are frequently associated with cancer progression. Here, we characterized the role of ERK/FOXM1 signaling in mediating the metastatic potential of ovarian cancer cells. Immunohistochemical (IHC), immunoblotting and semi-quantitative RT-PCR analyses found that both phospho-ERK and FOXM1 were frequently upregulated in ovarian cancers. Intriguingly, the overexpressed phospho-ERK (p<0.001) and FOXM1 (p<0.001) were significantly correlated to high-grade ovarian tumors with aggressive behavior such as metastasized lymph node (5 out of 6). Moreover, the expressions of phospho-ERK and FOXM1 had significantly positive correlation (p<0.001). Functionally, ectopic expression of FOXM1B remarkably enhanced cell migration/invasion, while FOXM1C not only increased cell proliferation but also promoted cell migration/invasion. Conversely, inhibition of FOXM1 expression by either thiostrepton or U0126 could significantly impair FOXM1 mediated oncogenic capacities. However, the down-regulation of FOXM1 by either thiostrepton or U0126 required the presence of p53 in ovarian cancer cells. Collectively, our data suggest that over-expression of FOXM1 might stem from the constitutively active ERK which confers the metastatic capabilities to ovarian cancer cells. The impairment of metastatic potential of cancer cells by FOXM1 inhibitors underscores its therapeutic value in advanced ovarian tumors.

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

“…Further analysis of metastatic lesions is required to determine whether metastatic cells also rely on YAP/TEAD/FOXM1. Of note, YAP and FOXM1 clearly play a role in cell migration/invasion and metastasis in other contexts (41,42), and, importantly, FOXM1 has been associated specifically with UPS metastasis (25). It will be interesting to determine whether YAP and FOXM1 coregulate metastatic progression beyond their control of proliferation in the primary tumor.…”

Genome and Transcriptome Sequencing in Prospective Metastatic Triple-Negative Breast Cancer Uncovers Therapeutic Vulnerabilities

“…FOXM1 is a transcriptional activator involved in proliferation, cell-cycle control, and mitosis, through the regulation of many genes involved in G 2 -M and mitotic checkpoint, such as AURKA, AURKB, PLK1, and CENPF among others (35). The FOXM1 gene was also recently highlighted as significantly deregulated in serous ovarian tumors and breast cancer (36)(37)(38).…”

Inhibition of FOXM1 by thiostrepton sensitizes medulloblastoma to the effects of chemotherapy

“…FOXM1 has been reported to play a central role in tumor metastasis (27)(28)(29), and few studies have explored the antitumor activity of thiostrepton. In our study, thiostrepton significantly decreased the migration and invasion capacity of Daoy cells.…”

“…FOXM1 play a critical role in tumor cell metastasis (27)(28)(29). Since tumor cell migration and invasion are essential steps in tumor metastasis, we further examined the effects of thiostrepton on cell migration and invasion in Daoy cells.…”