TNF‐α mediated MEK–ERK signaling in invasion with putative network involving NF‐κB and STAT‐6: a new perspective in glioma

Abstract

Glioblastoma is the most common malignant primary brain tumor with poor prognosis. Invasion involves pro-inflammatory cytokines and major signaling hubs. Tumor necrosis factor-α (TNF-α) acts as a master switch in establishing an intricate link between inflammation and cancer. The present study attempted to explore the possible implication of MAPK extracellular signaling-regulated kinase kinase (MEK)-extracellular signaling-regulated kinase (ERK) signaling pathway and expression of nuclear factor-κB (NF-κB), signal transducers and activators of transcription-6 (STAT-6), ERK, and phosphorylated-ERK (p-ERK) signaling proteins in TNF-α microenvironment. U0126 and PD98059 were used to inhibit the MEK-ERK1/2 pathway. TNF-α stimulation enhanced invasion in U87MG, U251MG and patient-derived primary glioma cells, whereas cell viability was not altered. Matrix metalloproteinase-2 (MMP-2) activity was increased only in U251MG glioma cells. These data suggest that TNF-α microenvironment plays an important role in the invasion of U251MG, U87MG, and patient-derived primary glioma cells, without any cytotoxic effect. The MMP-2 activity is differentially regulated by TNF-α stimulation in these cells. TNF-α stimulation upregulated the protein expression of ERK-1, ERK-2 and also increased the level of p-ERK1/2. TNF-α stimulation further upregulated the expression of NF-κB1, STAT-6 in tandem with Ras-MEK signaling system in U87MG cells, which emphasized the possible involvement of these signaling hubs in the glioma microenvironment. MEK-ERK inhibitors significantly attenuated the invasion of U87MG cells mediated by the TNF-α stimulation, probably through their inhibitory impact on p-ERK1/2 and ERK-2. This study provides the possible rationale of invasion by glioma cells in a TNF-α-induced proinflammatory milieu, which involves direct role of MEK-ERK signaling, with possible implication of NF-κB and STAT-6.

Time‑series clustering of cytokine expression after transarterial chemoembolization in patients with hepatocellular carcinoma

“…Cytokines are a broad and loose category of small proteins that include chemokines, interferons, interleukins, lymphokines and tumor necrosis factors (TNFs), and are produced and released by different cells in the liver; cytokines play an important role in inflammation and tumor progression (8). As such, TNF-α acts as a master switch in establishing an intricate link between proinflammation and disease progression in patients with glioblastoma (9). Through a granulocyte-macrophage colony-stimulating factor-and interleukin (IL)-5-dependent mechanism, obesity-mediated low-grade inflammation increases breast cancer metastasis to the lung (10).…”

Evaluation of the Expression Levels of Cannabinoid Type-1 (CB1) Receptor and Phosphorylated Extracellular Signal-Regulated Kinase (p-ERK) in Gliomas

“…Even though we did not see an overexpression in CB1R in tumors, the activation of ERK by phosphorylation can be due to the activation of several other signaling pathways [47]. Previous studies have described the activation of MAPK/ERK pathway and its involvement in the development of many types of cancers including breast cancer [48], gastric cancer [49], non-small cell lung cancer [50], gallbladder tumors [51] and gliomas [52]. Future studies on glioma could tackle the activation of ERK and role of CB1R in this regard.…”

MiR-18a-downregulated RORA inhibits the proliferation and tumorigenesis of glioma using the TNF-α-mediated NF-κB signaling pathway

“…Recent studies reported that inflammation plays an important role in the occurrence, development, and prognosis of glioma [41À44]. TNF-a is a major regulator of inflammation, and is overexpressed and secreted in the tumor microenvironment [45]. TNF-a promotes the proliferation, migration, and treatment resistance of glioma via activating NF-kB signaling [46,47].…”