Oxaliplatin treatment impairs extension of sensory neuron neuritesin vitrothrough miR-204 overexpression

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Abstract

Oxaliplatin is a platinum-based drug used in the treatment of gastric cancers. Oxaliplatin treatment induces sensory neuropathy characterized by cold hypersensibility in the acute phase and sensory impairment when the neuropathy becomes chronic. In order to determine the effect of oxaliplatin on sensory neurons, we used an in vitro model in which oxaliplatin treatment reduced arborization of dorsal root ganglia neurons in a dose-dependent manner. Moreover, we characterized the role of microRNAs in oxaliplatin induced-neuropathy. In particular, we focused on microRNAs that control the expression of axon guidance molecules, and therefore, regulate neurite arborization. As a result, we highlighted the upregulation of miR-204, a microRNA that controls the expression of PlexinA2, a semaphorin receptor involved in neurite guidance. Interaction of miR-204 and Plexin A2 was confirmed by luciferase assay. In addition, overexpression of miR-204 in dorsal root ganglia neuron cultures reduced length and extension of neurites and also reduced Plexin A2 labelling without increasing apoptosis rate. On the other hand, sequestration of miR-204 by a specific microRNA sponge increases neurite length and PlexinA2 expression. Taken together, our data indicate that oxaliplatin impairs sensory neurons arborization through up-regulation of miR-204 that decreases PlexinA2 expression and neurite length.

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