Purpose: Forkhead 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 methods: We 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. Results: The 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. Conclusion: Expression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process.

Glutamate is well-known as metabolite for maintaining the energy and redox homeostasis in cancer, moreover it is also the primary excitatory neurotransmitter in the central nervous system. However, whether glutamatergic signaling can regulate hepatocellular carcinoma (HCC) progression and the specific regulatory mechanisms are unknown. In the present study, we found that glutamate and its receptor NMDAR2B were significantly elevated in HCC patients, which predicts poor prognosis. Glutamate could upregulate CCL2 expression on hepatoma cells and further enhance the capability of tumor cells to recruit tumor-associated macrophages (TAMs). Mechanistically, glutamate could facilitate CCL2 expression through NMDAR pathway by decreasing the expression of EZH2, which regulates the H3K27me3 levels on the CCL2 promoter, rather than affecting DNA methylation. Moreover, inhibiting glutamate pathway with MK801 could significantly delay tumor growth, with reduced TAMs in implanted Hepa1-6 mouse HCC models. Our work suggested that glutamate could induce CCL2 expression to promote TAM infiltration by negatively regulating EZH2 levels in hepatoma cells, which might serve as a potential prognostic marker and a therapeutic target for HCC patients.

Forkhead box (FOX)K2 (FOXK2) is a member of the FOX transcription factor family. It has been suggested previously that FOXK2 is required to suppress tumor growth; however, the exact role of FOXK2 in gastric cancer remains to be elucidated. In the present study, the association between FOXK2 expression and the clinicopathological characteristics of patients with gastric cancer was investigated. The prognostic value of FOXK2 expression and the significance of clinicopathological parameters in the overall survival (OS) and progression‑free survival of patients were also determined by survival analysis. To investigate the functional roles of FOXK2, it was downregulated in BGC‑823 cells using small interfering (si)RNA, and upregulated using a FOXK2 plasmid. Colony formation, Cell Counting Kit‑8 and cell proliferation analyses were conducted to examine the proliferation of gastric cancer cells. Transwell and wound‑healing assays were performed to investigate the effect of FOXK2 expression on gastric cancer cell migration and invasion. The clinical data demonstrated that FOXK2 expression was reduced in high‑grade gastric cancer tissues, and a low level of FOXK2 expression indicated a poor prognosis. The data obtained from the Human Protein Atlas revealed that patients with gastric cancer and a high level of FOXK2 expression had a longer OS time. The results of colony formation assays, Transwell and wound healing assays demonstrated that FOXK2 repressed the proliferation, invasion and migration of gastric cancer cells, respectively. The findings indicated that FOXK2 may serve as a promising therapeutic target in gastric cancer. Taken together, the findings of the present study demonstrated that FOXK2 functions as a tumor suppressor in gastric cancer; the loss of FOXK2 may induce the growth and invasion of gastric cancer cells.

Tyrosine phosphatase receptor type N (PTPRN) plays an important role in the regulation of the secretion pathways of various neuroendocrine cells. Moreover, PTPRN was demonstrated to play a crucial role in the initiation and progression of the signalling cascade regulating cell function. In this study, fifty-seven glioma patients were enrolled for clinical and prognostic analyses. The cell phenotype was determined by cell proliferation and migration assays. RNA-seq, co-IP and mass spectrometry were used to study the molecular mechanism of the effects of PTPRN on cell proliferation and metastasis. The result showed that High expression of PTPRN indicated a poor prognosis of high-grade glioma. PTPRN downregulation reduced the proliferation and migration of glioma cells, and PTPRN overexpression induced the proliferation and migration of glioma cells. PTPRN knockdown decreased tumor growth in a mouse xenograft model. Effect of PTPRN knockdown on the transcriptome was studied in U87 glioma cells. PTPRN activated the PI3K/AKT pathway by interacting with HSP90AA1. In conclusion, PTPRN is an important proliferation- and metastasis-promoting factor. Reducing the expression of PTPRN in glioma cells can be used as a potential therapeutic strategy.