Abstract
Aberrant expression of Fos-related antigen-1 (Fra1) is commonly elevated in various malignant cancers and is strongly implicated in invasion and metastasis. However, the molecular mechanisms underlying its dysregulation in human glioma remain poorly understood. In the present study, we demonstrate that up-regulation of Fra1 plays a crucial role in the glioma aggressiveness and epithelial–mesenchymal transition (EMT) activated by Wnt/β-catenin signal pathway. In glioma cells, activation of Wnt/β-catenin signalling by Wnt3a administration obviously induced EMT and directly activated the transcription of Fra1. Phenotype experiments revealed that up-regulation of Fra1 induced by Wnt/β-catenin signalling drove the EMT of glioma cells. Furthermore, it was found that the cisplatin resistance acquired by Wnt/β-catenin signalling activation depended on increased expression of Fra1. Analysis of clinical specimens verified a positive correlation between Fra1 and β-catenin as well as a poor prognosis in glioma patients with double-high expressions of them. These findings indicate that an aberrant Wnt/β-catenin signalling leads to the EMT and drug resistance of glioma via Fra1 induction, which suggests novel therapeutic strategies for the malignant disease.
Highlights
IntroductionMalignant glioma (MG) is one of the most aggressive tumours and occurs frequently in the central nervous system [1]
Among various human cancers, malignant glioma (MG) is one of the most aggressive tumours and occurs frequently in the central nervous system [1]
The above findings reveal that up-regulation of Fos-related antigen-1 (Fra1) by Wnt3a is indispensible for the epithelial–mesenchymal transition (EMT) induced by Wnt/β-catenin signalling in glioma cells
Summary
Malignant glioma (MG) is one of the most aggressive tumours and occurs frequently in the central nervous system [1]. Lethality in glioma patients is caused by metastasis involving migration and invasion of cancer cells, which results in resistance to the existing drugs [3]. It has been reported that the EMT-related transcription factors (EMT-TFs) including Slug, Snail, ZEB1 and Twist are indispensable for EMT process [6,7,8,9]. As another important factor, Fos-related antigen-1 (Fra1) always indicates metastasis and poor prognosis in a variety of human cancers. Different from other members of the Fos family, Fra is closely related with the motile and invasive phenotypes of cancer cells [10].
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