miR-34c-5p functions as pronociceptive microRNA in cancer pain by targeting Cav2.3 containing calcium channels

• Verfasst von: Gandla, Jagadeesh [VerfasserIn]
• Verfasst von: Kuner, Rohini [VerfasserIn]
• Verfasst von: Bali, Kiran Kumar [VerfasserIn]
• Titel: miR-34c-5p functions as pronociceptive microRNA in cancer pain by targeting Cav2.3 containing calcium channels
• Verf.angabe: Jagadeesh Gandla, Santosh Kumar Lomada, Jianning Lu, Rohini Kuner, Kiran Kumar Bali
• Umfang: 15 S.
• Fussnoten: Gesehen am 15.06.2018
• Titel Quelle: Enthalten in: Pain
• Jahr Quelle: 2017
• Band/Heft Quelle: 158(2017), 9, S. 1765-1779
• ISSN Quelle: 1872-6623
• DOI: doi:10.1097/j.pain.0000000000000971
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1576393909

Abstract

Pathophysiological mechanisms underlying pain associated with cancer are poorly understood. microRNAs (miRNAs) are a class of noncoding RNAs with emerging functional importance in chronic pain. In a genome-wide screen for miRNAs regulated in dorsal root ganglia (DRG) neurons in a mouse model of bone metastatic pain, we identified miR-34c-5p as a functionally important pronociceptive miRNA. Despite these functional insights and therapeutic potential for miR-34c-5p, its molecular mechanism of action in peripheral sensory neurons remains unknown. Here, we report the identification and validation of key target transcripts of miRNA-34c-5p. In-depth bioinformatics analyses revealed Cav2.3, P2rx6, Oprd1, and Oprm1 as high confidence putative targets for miRNA-34c-5p. Of these, canonical and reciprocal regulation of miR-34c-5p and Cav2.3 was observed in cultured sensory neurons as well as in DRG in vivo in mice with cancer pain. Coexpression of miR-34c-5p and Cav2.3 was observed in peptidergic and nonpeptidergic nociceptors, and luciferase reporter assays confirmed functional binding of miR-34c-5p to the 3′ UTR of Cav2.3 transcripts. Importantly, knocking down the expression of Cav2.3 specifically in DRG neurons led to hypersensitivity in mice. In summary, these results show that Cav2.3 is a novel mechanistic target for a key pronociceptive miRNA, miR-34c-5p, in the context of cancer pain and indicate an antinociceptive role for Cav2.3 in peripheral sensory neurons. The current study facilitates a deeper understanding of molecular mechanisms underlying cancer pain and suggests a potential for novel therapeutic strategies targeting miR-34c-5p and Cav2.3 in cancer pain.