Forkhead box K2 inhibits the proliferation, migration, and invasion of human glioma cells and predicts a favorable prognosis

Abstract

PurposeForkhead box K2 (FOXK2) is a member of the forkhead box family of transcription factors. Recently, researchers discovered that overexpression of FOXK2 inhibits the proliferation and metastasis of breast cancer, non-small cell lung cancer, and colorectal cancer, and is related to the clinical prognosis. However, in hepatocellular carcinoma, FOXK2 results in the opposite phenotypes. Currently, the contribution of FOXK2 to glioma pathogenesis is not clear.Patients and methodsWe evaluated the expression of FOXK2 in 151 glioma patients using immunohistochemistry assays. The associations among the expression of FOXK2, clinicopathological parameters, and the prognosis of glioma patients were statistically analyzed. We downregulated and upregulated the level of FOXK2 in glioma cells by transfections with small interfering RNA and plasmids. Then, we investigated the effects on tumor cell behavior in vitro by Cell Counting Kit-8 assays, colony-formation assay, transwell assay, and the epithelial-to-mesenchymal transition (EMT) biomarker levels.ResultsThe clinical data showed that expression of FOXK2 gradually decreased with increasing World Health Organization (WHO) grades and a low level of FOXK2 indicates a poor prognosis. FOXK2 expression is negatively correlated with Ki67 expression and the WHO degree but is not correlated with other clinicopathological parameters, including sex, age, Karnofsky Performance Status, tumor diameter, O-6-methylguanine-DNA methyltransferase, and glutathione S-transferase pi. FOXK2 knockdown enhances glioma cell proliferation, migration, invasion, and EMT process, and, in contrast, FOXK2 overexpression inhibits glioma cell proliferation, migration, invasion, and the EMT process.ConclusionExpression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process.

FOXK2 Transcription Factor and Its Emerging Roles in Cancer

“…This is consistent with data obtained in gastric cancer cells, where FOXK2 overexpression has been demonstrated to induce early apoptosis and inhibit cell growth, migration and invasion, which is accompanied by an E-cadherin increase and a N-cadherin decrease [46]. Similar conclusions have been derived from FOXK2 knockdown studies, where loss of FOXK2 promotes growth, invasion and migration in glioma cells, followed by modulation of expression of E-cadherin, N-cadherin and vimentin EMT markers [47]. Consistent with these findings, Chen and colleagues [44] have reported that FOXK2 overexpression in lung cancer-derived cell lines leads to upregulation of E-cadherin and α-catenin along with downregulation of N-cadherin and vimentin (Figure 5), suggesting that FOXK2 might modulate the expression of epithelial and mesenchymal markers closely linked to the EMT process.…”

“…FOXK2 mRNA expression has been found to be downregulated in high-grade, compared to low-grade glioma [47]. Also, FOXK2 protein expression is negatively associated with tumour grade and staining of KI-67 proliferation marker and positively correlated with favorable prognosis in both uni- and multivariate analysis [47].…”

“…FOXK2 mRNA expression has been found to be downregulated in high-grade, compared to low-grade glioma [47]. Also, FOXK2 protein expression is negatively associated with tumour grade and staining of KI-67 proliferation marker and positively correlated with favorable prognosis in both uni- and multivariate analysis [47]. A positive correlation of FOXK2 protein expression with good prognosis has also been observed in gastric cancer, in which FOXK2 levels have been seemingly associated with tumour differentiation [46].…”

Epigenetically Upregulated MicroRNA-602 Is Involved in a Negative Feedback Loop with FOXK2 in Esophageal Squamous Cell Carcinoma

“…These results were also consistent with a previous report that suggested that lower FOXK2 expression significantly induced the migration of other cancer cell types. [38][39][40][41][42][43] In summary, our study reported, for the first time, that increased expression of miR-602 caused by its promoter hypomethylation is functionally associated with the potency of growth and metastasis in ESCC by regulating FOXK2. Moreover, serum miR-602 might provide a novel and stable marker and act as an independent predictor of OS for patients with ESCC.…”

“…38 Recent researchers discovered that overexpression of FOXK2 inhibits the proliferation and metastasis of breast cancer, lung cancer, and hepatocellular cancer and is related to the clinical prognosis. [38][39][40] FOXK2 is involved in several signaling pathways, such as the mammalian target of rapamycin-, WNT-, AKT-, and EMT-signaling pathways. These signaling pathways regulate cell proliferation and death by influencing the expression of important genes through the transcription repressor FOXK2.…”