State Key Laboratory of Oncology in Southern China, Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
Department of Anesthesiology, Zhongshan People's Hospital, Zhongshan, 528400, Guangdong, China.
Mol Neurobiol. 2023 Oct;60(10):5672-5690. doi: 10.1007/s12035-023-03398-5. Epub 2023 Jun 19.
Chemotherapy-induced neuropathic pain (CINP) is a dose-limiting adverse event affecting 40% of chemotherapy patients. MiRNA-mRNA interaction plays an important role in various processes. However, detailed profiling of miRNA-mRNA interactions in CINP remains unclear. Here, a rat-based CINP model was established using paclitaxel, followed by nociceptive behavioral tests related to mechanical allodynia, thermal hyperalgesia, and cold allodynia. The landscape of miRNA-mRNA interaction in the spinal dorsal horn was investigated through mRNA transcriptomics and small RNA sequencing. Under CINP condition, 86 differentially expressed mRNAs and 56 miRNAs were identified. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated the activity of Odorant binding, postsynaptic specialization and synaptic density, extracellular matrix, mitochondrial matrix, retrograde endocannabinoid signaling, and GTPase activity. Protein-protein interaction (PPI), networks of circRNA-miRNA-mRNA, lncRNA-miRNA-mRNA, and TF-genes were demonstrated. We next explored the immune infiltration microenvironment and found a higher infiltration abundance of Th17 and a lower abundance of MDSC in CINP. RT-qPCR and dual-luciferase assays were used to verify the sequencing results, and single-cell analysis based on the SekSeeq database was conducted. Combined with bioinformatics analyses and experimental validations, Mpz, a protein-coding gene specifically expressed in Schwann cells, was found critical in maintaining CINP under miRNA regulation. Therefore, these data highlight the expression patterns of miRNA-mRNA, and the underlying mechanism in the spinal dorsal horn under CINP condition, and Mpz may serve as a promising therapeutic target for patients with CINP.
化疗诱导性神经病理性疼痛（CINP）是一种限制剂量的不良事件，影响 40%的化疗患者。miRNA-mRNA 相互作用在各种过程中起着重要作用。然而，CINP 中 miRNA-mRNA 相互作用的详细分析仍不清楚。在这里，我们使用紫杉醇建立了基于大鼠的 CINP 模型，然后进行了与机械性痛觉过敏、热痛觉过敏和冷痛觉过敏相关的痛觉行为测试。通过 mRNA 转录组学和小 RNA 测序研究了脊髓背角中 miRNA-mRNA 相互作用的图谱。在 CINP 条件下，鉴定出 86 个差异表达的 mRNAs 和 56 个 miRNAs。基因集富集分析（GSEA）、基因本体论（GO）和京都基因与基因组百科全书（KEGG）途径富集分析表明，气味结合、突触后特化和突触密度、细胞外基质、线粒体基质、逆行内源性大麻素信号和 GTP 酶活性等途径的基因是活跃的。还展示了蛋白-蛋白相互作用（PPI）网络、circRNA-miRNA-mRNA、lncRNA-miRNA-mRNA 和 TF-基因网络。接下来，我们探索了免疫浸润微环境，发现 CINP 中 Th17 的浸润丰度较高，MDSC 的丰度较低。使用 RT-qPCR 和双荧光素酶报告基因检测验证测序结果，并基于 SekSeeq 数据库进行单细胞分析。结合生物信息学分析和实验验证，发现编码 Schwann 细胞特异性表达的蛋白基因 Mpz 在 miRNA 调控下对维持 CINP 至关重要。因此，这些数据突出了 miRNA-mRNA 的表达模式以及 CINP 条件下脊髓背角的潜在机制，Mpz 可能成为 CINP 患者有前途的治疗靶点。
