miR-199a-3p suppresses neuroinflammation by directly targeting MyD88 in a mouse model of bone cancer pain

Mohamed J. Saadh, Amera Bekhatroh Rashed, Azfar Jamal, Roxana Yolanda Castillo-Acobo, Mohammad Azhar Kamal, Juan Carlos Cotrina-Aliaga, José Luis Arias Gonzáles, Abdulaziz S. Alothaim, Wardah A. Alhoqail, Fuzail Ahmad, Natrayan Lakshmaiya, Ali H. Amin, Dhuha Ghassan Younus, Gregorio Gilmer Rosales Rojas, Abolfazl Bahrami, Reza Akhavan-Sigari

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Pain is a profoundly debilitating symptom in cancer patients, leading to disability, immobility, and a marked decline in their quality of life. This study aimed to investigate the potential roles of miR-199a-3p in a murine model of bone cancer pain induced by tumor cell implantation in the medullary cavity of the femur. Materials and methods: We assessed pain-related behaviors, including the paw withdrawal mechanical threshold (PWMT) and the number of spontaneous flinches (NSF). To investigate miRNA expression and its targets in astrocytes, we employed a combination of RNA-seq analysis, qRT-PCR, Western blotting, EdU, TUNEL, ChIP, ELISA, and luciferase reporter assays in mice (C3H/HeJ) with bone cancer pain and control groups. Key findings: On days 10, 14, 21, and 28 post-surgery, we observed significant differences in PWTL, PWMT, and NSF when compared to the sham group (P < 0.001). qRT-PCR assays and miRNA sequencing results confirmed reduced miR-199a-3p expression in astrocytes of mice with bone cancer pain. Gain- and loss-of-function experiments demonstrated that miR-199a-3p suppressed astrocyte activation and the expression of inflammatory cytokines. In vitro investigations revealed that miR-199a-3p mimics reduced the levels of inflammatory factors in astrocytes and MyD88/NF-κB proteins. Furthermore, treatment with a miR-199a-3p agonist resulted in reduced expression of MyD88, TAK1, p-p65, and inflammatory mediators, along with decreased astrocyte activation in the spinal cord. Significance: Collectively, these findings demonstrate that upregulation of miR-199a-3p may offer a therapeutic avenue for mitigating bone cancer pain in mice by suppressing neuroinflammation and inhibiting the MyD88/NF-κB signaling pathway.

Original languageEnglish
Article number122139
JournalLife Sciences
Volume333
DOIs
StatePublished - 15 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • Astrocyte activation
  • Bone cancer pain
  • MyD88
  • NF-κB signaling pathway
  • Neuroinflammation
  • miR-199a-3p

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