Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma.

OBJECTIVES: Perineural invasion is a prominent clinical feature of various cancers, which causes difficulty in curative resection. Glial cell-derived neurotrophic factor (GDNF), a potent neurotrophic factor, plays an important role in the invasive and metastatic behavior of various cancers. The aim of this study was to examine the role of GDNF on oral squamous cell carcinoma. MATERIALS AND METHODS: GDNF expression in tissue samples was analyzed by immunohistochemistry. Transwell assay, zymography, Western blot, reverse transcription-PCR, and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of GDNF on oral cancer cells. RESULTS: Human oral cancer tissues showed higher GDNF expression than that in normal tissues. We also found that application of human GDNF enhanced the cell migration ability of human oral cancers. Moreover, treatment with GDNF increased matrix metalloproteinase (MMP)-9 and MMP-13 expression in oral cancer. Inhibition of MMP-9 and MMP-13 in oral cancer cells by pharmacological inhibitors or neutralizing antibodies reduced GDNF-enhanced cell migration. Moreover, transfection with siRNA against MMP-13 inhibited GDNF-enhanced cell migration. Treatment with GDNF also increased ERK, p38 and JNK phosphorylation, and AP-1 DNA binding activity in human oral cancer cells. Inhibition of MAP kinase or AP-1 also reduced GDNF-induced oral cancer cell migration. In migration-prone sublines, oral cancer cells showed a higher migration ability than that of the original oral cancer cells. Surprisingly, the enhancement of cell migratory activity in migration-prone sublines was reduced by a GDNF-neutralizing antibody. Importantly, migration-prone sublines of oral cancer revealed higher GDNF expression. CONCLUSION: These results indicate a regulatory effect on cell migration by GDNF in oral squamous cancer.

The roles of glial cell line-derived neurotrophic factor, tumor necrosis factor-alpha, and an inducer of these factors in drug dependence.

There are few efficacious medications for drug dependence at present. Recent evidence has suggested that various cytokines are involved in the effects of abused drugs, suggesting that these factors play a role in drug dependence. In this article, the roles of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-alpha (TNF-alpha) in drug dependence are discussed. GDNF inhibits the cocaine-induced upregulation of tyrosine hydroxylase activity in the ventral tegmental area and blocks behavioral responses to cocaine. TNF-alpha attenuates rewarding effects and locomotor sensitization induced by methamphetamine (METH) and morphine (MOR). Moreover, we mentioned the potential of Leu-Ile, which induces the expression of GDNF and TNF-alpha, as a novel therapeutic agent for drug dependence. Leu-Ile inhibits not only the development but also the maintenance of METH- or MOR-induced place preference and locomotor sensitization in mice. The inhibitory effect of Leu-Ile on METH- or MOR-induced place preference is not observed in GDNF heterozygous and TNF-alpha knockout mice. Leu-Ile inhibits METH- or MOR-induced place preference and sensitization by attenuating the METH- or MOR-induced increase in extracellular dopamine levels in the nucleus accumbens via the induction of GDNF and TNF-alpha expression. These findings suggest that Leu-Ile could be a novel therapeutic agent for drug dependence.