Abstract：
Triple-negative breast cancer (TNBC) is an exceptionally aggressive breast cancer subtype associated with neuropathic pain. This study explores the effects of 5\'-nucleotidase domain-containing protein 2 (NT5DC2) on the progression of TNBC and neuropathic pain. Microarray analysis was conducted to identify differentially expressed genes in TNBC and the pathways involved. Gain- and loss-of-function assays of NT5DC2 were performed in TNBC cells, followed by detection of the extracellular acidification rate, adenosine triphosphate (ATP) levels, lactic acid production, glucose uptake, proliferation, migration, and invasion in TNBC cells. Macrophages were co-cultured with TNBC cells to examine the release of polarization-related factors and cytokines. A xenograft tumor model was established for in vivo validation. In addition, a mouse model of neuropathic pain was established through subepineural injection of TNBC cells, followed by measurement of the sciatic functional index and behavioral analysis to assess neuropathic pain. NT5DC2 was upregulated in TNBC and was positively correlated with epidermal growth factor receptor (EGFR). NT5DC2 interacted with EGFR to promote downstream signal transduction in TNBC cells. NT5DC2 knockdown diminished proliferation, migration, invasion, the extracellular acidification rate, ATP levels, lactic acid production, and glucose uptake in TNBC cells. Co-culture with NT5DC2-knockdown TNBC cells alleviated the M2 polarization of macrophages. Furthermore, NT5DC2 knockdown reduced tumor growth and neuropathic pain in mice. Importantly, activation of the EGFR pathway counteracted the effects of NT5DC2 knockdown. NT5DC2 knockdown protected against TNBC progression and neuropathic pain by inactivating the EGFR pathway.
摘要：
三阴性乳腺癌（TNBC）是与神经性疼痛相关的异常侵袭性乳腺癌亚型。这项研究探讨了含5'-核苷酸酶结构域的蛋白2（NT5DC2）对TNBC和神经性疼痛进展的影响。进行微阵列分析以鉴定TNBC中差异表达的基因和所涉及的途径。在TNBC细胞中进行NT5DC2的功能增益和丧失测定，然后检测细胞外酸化率，三磷酸腺苷（ATP）水平，乳酸生产，葡萄糖摄取，扩散,迁移,和入侵TNBC细胞。巨噬细胞与TNBC细胞共培养以检测极化相关因子和细胞因子的释放。建立异种移植肿瘤模型用于体内验证。此外,通过神经下注射TNBC细胞建立小鼠神经病理性疼痛模型,然后测量坐骨神经功能指数和行为分析以评估神经性疼痛。NT5DC2在TNBC中上调,与表皮生长因子受体(EGFR)呈正相关。NT5DC2与EGFR相互作用促进TNBC细胞下游信号转导。NT5DC2敲低减少增殖，迁移,入侵,胞外酸化率，ATP水平,乳酸生产，和TNBC细胞的葡萄糖摄取。与NT5DC2敲低的TNBC细胞共培养减轻了巨噬细胞的M2极化。此外，NT5DC2敲低可降低小鼠的肿瘤生长和神经性疼痛。重要的是,EGFR通路的激活抵消了NT5DC2敲低的影响.NT5DC2敲低通过灭活EGFR途径保护免受TNBC进展和神经性疼痛。
