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.

中文翻译：

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NT5DC2 敲除通过阻断 EGFR 通路抑制三阴性乳腺癌的进展、糖酵解和神经性疼痛

三阴性乳腺癌（TNBC）是一种与神经性疼痛相关的异常侵袭性乳腺癌亚型。本研究探讨了含 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。进行微阵列分析以确定 TNBC 中差异表达的基因及其相关途径。在TNBC细胞中进行NT5DC2的功能获得和丧失功能测定，然后检测TNBC细胞的细胞外酸化率、三磷酸腺苷（ATP）水平、乳酸产生、葡萄糖摄取、增殖、迁移和侵袭。巨噬细胞与 TNBC 细胞共培养，以检查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，通过腰膜下注射TNBC细胞建立小鼠神经病理性疼痛模型，然后通过测量坐骨功能指数和行为分析来评估神经病理性疼痛。NT5DC2在TNBC中表达上调，并与表皮生长因子受体（EGFR）呈正相关。NT5DC2 与 EGFR 相互作用，促进 TNBC 细胞中的下游信号转导。NT5DC2敲除降低了TNBC细胞的增殖、迁移、侵袭、细胞外酸化率、ATP水平、乳酸产生和葡萄糖摄取。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 敲低可减少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 敲低可通过灭活 EGFR 通路来防止 TNBC 进展和神经性疼痛。