Abstract
This study aimed to evaluate the biological role of forkhead box N3 (FOXN3) in human glioma and clarify the possible molecular mechanisms. FOXN3 expression patterns in clinical tissue specimens were characterized via qPCR and Western blotting. Kaplan-Meier survival curve was applied to assess the correlation between FOXN3 expression and overall survival. Effects of FOXN3 over-expression and depletion on glioma cell proliferation, apoptosis, migration and invasion were assessed by CCK8, colony formation assay, flow cytometry, scratch wound healing assay and Transwell invasion assay, respectively. Moreover, the involvement of AKT/murine double minute 2 (MDM2)/p53 pathway was evaluated. Additionally, tumor transplantation model assay was performed to determine the effects of FOXN3 over-expression on glioma cell growth in vivo. Results showed that FOXN3 was significantly down-regulated in glioma tissues compared with normal tissues. Patients with lower FOXN3 expression exhibited a shorter overall survival time. Gain- and loss-of-function analyses demonstrated that FOXN3 over-expression significantly suppressed proliferation, survival and motility of glioma cells, whereas FOXN3 knockdown remarkably promoted glioma cell proliferation, survival and motility. Furthermore, FOXN3 over-expression inhibited the activation of AKT/MDM2/p53 signaling pathway in glioma cells, while FOXN3 depletion facilitated its activation. Additionally, tumor xenograft assays revealed that FOXN3 over-expression retarded glioma cell growth in vivo. Collectively, these findings indicate that FOXN3 inhibits cell growth and invasion through inactivating the AKT/MDM2/p53 signaling pathway and that FOXN3-AKT/MDM2/p53 axis may represent a novel therapeutic target for glioma patients.
Highlights
Human glioma has emerged as one of the most common intracranial malignancies in recent decades, accounting for roughly 45% of all brain tumors [1,2,3]
It is well documented that Forkhead box N3 (FOXN3) belongs to the FOX family of transcriptional factors, which are implicated in a great variety of biological activities, including cell survival, cell proliferation and cell migration as well as cell invasion [10,11,12]
Kaplan-Meier survival curve was adopted to analyze the link between FOXN3 mRNA expression and overall survival time of glioma patients
Summary
Human glioma has emerged as one of the most common intracranial malignancies in recent decades, accounting for roughly 45% of all brain tumors [1,2,3]. In spite of the fact that great advances regarding the standardized therapies have been made for glioma patients, the long-term prognosis of malignant glioma patients is still pretty frustrating [7,8,9]. Recent studies have uncovered that FOXN3 functions as a key www.aging-us.com player in multiple kinds of malignant tumors, such as papillary thyroid cancer [13], tongue squamous cell carcinoma [14], melanoma [15] and breast cancer [16]. Potential biological functions of FOXN3 in human glioma remain largely unclear
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