Chemotherapy resistance is a leading cause of treatment failure in cases of cervical adenocarcinoma (ADC), and no effective treatment approach has yet been found. We previously identified the differentially expressed kynureninase (KYNU) mRNA in cervical adenocarcinoma cells (HeLa) and cervical adenocarcinoma cisplatin resistance cells (HeLa/DDP) using gene chips. However, the role and potential mechanism of KYNU in the cisplatin resistance of cervical adenocarcinoma remain unclear. We verified the expression of KYNU in the cells and tissues of ADC patients and analyzed its correlation with patient prognosis. A stable HeLa/DDP cell line with KYNU mRNA knockdown was constructed. We then used a CCK8 assay to detect cell survival, a transwell assay to evaluate cell migration and proliferation and flow cytometry to measure apoptosis. The effect of KYNU silence on cisplatin sensitivity was evaluated in an orthotopic model of metastatic ADC. Immunohistochemistry was performed to determine the changes in relevant drug resistance-associated protein expression, aiming to explore the underlying mechanism of KYNU-mediated drug resistance. KYNU is overexpressed in HeLa/DDP cells and tissues and is associated with the poor prognoses of patients with ADC. After KYNU mRNA knockdown, the invasion, migration, and proliferation of HeLa/DDP cells in the cisplatin environment significantly reduced, while the apoptosis rate of HeLa/DDP cells significantly increased. Meanwhile, KYNU knockdown improved the DDP sensitivity of ADC in vivo. Furthermore, silencing KYNU decreased the expressions of CD34 and the drug-resistance related proteins P-gp, MRP1, and GST-π and increased the level of the proapoptotic regulatory protein Bax. KYNU deficiency enhanced DDP sensitivity by suppressing cell proliferation, migration, and invasion and promoting apoptosis in DDP-resistant ADC cells in vitro. Furthermore, KYNU knockdown improved the drug sensitivity of ADC in vivo. The results showed that KYNU is involved in the chemotherapy resistance of cervical adenocarcinoma.

中文翻译：

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犬尿氨酸酶敲低可抑制体内和体外顺铂耐药并影响宫颈腺癌的预后

化疗耐药是宫颈腺癌（ADC）治疗失败的主要原因，目前尚未找到有效的治疗方法。我们之前使用基因芯片鉴定了宫颈腺癌细胞（HeLa）和宫颈腺癌顺铂耐药细胞（HeLa/DDP）中差异表达的犬尿氨酸酶（KYNU）mRNA。然而，KYNU在宫颈腺癌顺铂耐药中的作用和潜在机制仍不清楚。我们验证了 KYNU 在 ADC 患者细胞和组织中的表达，并分析了其与患者预后的相关性。构建了 KYNU mRNA 敲低的稳定 HeLa/DDP 细胞系。然后，我们使用 CCK8 测定来检测细胞存活，使用 Transwell 测定来评估细胞迁移和增殖，并使用流式细胞术来测量细胞凋亡。在转移性 ADC 的原位模型中评估了 KYNU 沉默对顺铂敏感性的影响。通过免疫组织化学测定相关耐药相关蛋白表达的变化，旨在探讨KYNU介导的耐药的潜在机制。KYNU 在 HeLa/DDP 细胞和组织中过度表达，与 ADC 患者的不良预后相关。KYNU mRNA敲低后，HeLa/DDP细胞在顺铂环境中的侵袭、迁移和增殖显着降低，而HeLa/DDP细胞的凋亡率显着增加。同时，KYNU敲低提高了ADC体内DDP敏感性。此外，沉默 KYNU 会降低 CD34 和耐药相关蛋白 P-gp、MRP1 和 GST-π 的表达，并增加促凋亡调节蛋白 Bax 的水平。KYNU 缺陷通过抑制细胞增殖、迁移和侵袭并促进体外 DDP 耐药 ADC 细胞凋亡来增强 DDP 敏感性。此外，KYNU 敲低提高了 ADC 体内的药物敏感性。结果表明KYNU参与宫颈腺癌的化疗耐药。