BackgroundAntiapoptosis is a major factor in the resistance of tumor cells to chemotherapy and radiotherapy. Thus, activation of cell pyroptosis may be an effective option to deal with antiapoptotic cancers such as esophageal adenocarcinoma (EAC).MethodsDifferential expression of ubiquitin‐like versus PHD and ring finger structural domain 1 (UHRF1) in EAC and near normal tissues was analyzed, as well as the prognostic impact on survival in EAC. Also, the same study was done for globular adiponectin (gAD). Simultaneously, the mRNA expression of UHRF1 was observed in different EAC cell lines. Real time cellular analysis (RTCA) was used to detect cell proliferation, and flow cytometry and inverted fluorescence microscopy were used to detect pyroptosis. Biocredit analysis was conducted to observe the correlation between UHRF1 and key pyroptosis proteins. OD values and CCK8 assay were used to determine the effect of miR‐378a‐3p on EAC cells. Quantitative real‐time polymerase chain reaction and Western blot were used to detect the correlation between UHRF1, gAD, and miR‐378a‐3p in EAC cells. Moreover, in vivo and in vitro experiments were performed to detect the relevant effects on tumor migration and invasion after inhibiting UHRF1 expression.ResultsUHRF1 was negatively correlated with the survival of patients with EAC, while miR‐378a‐3p showed the opposite effect. Additionally, gAD promoted EAC cell pyroptosis, upregulated miR‐378a‐3p, and significantly inhibited the proliferation of EAC cells. gAD directly reduced UHRF1 expression in EAC cells by upregulating miR‐378a‐3p. In cell migration and invasion assays, inhibition of UHRF1 expression significantly suppressed EAC cell metastasis. In animal experiments, we again demonstrated that gAD induced pyroptosis in EAC cells by inhibiting the expression of UHRF1.ConclusiongAD‐induced upregulation of miR‐378a‐3p significantly inhibited the proliferation of EAC by targeting UHRF1. Therefore, gAD may serve as an alternative therapy for chemotherapy‐ and radiation‐refractory EAC or other cancers with the same mechanism of pyroptosis action.

中文翻译：

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球状脂联素通过 miR-378a-3p/UHRF1 轴诱导食管腺癌细胞焦亡

研究背景抗凋亡是肿瘤细胞对化疗和放疗产生抵抗的主要因素。因此，激活细胞焦亡可能是治疗食管腺癌（EAC）等抗凋亡癌症的有效选择。方法分析了 EAC 和附近正常组织中泛素样与 PHD 和无名指结构域 1 (UHRF1) 的差异表达，以及对 EAC 生存的预后影响。此外，还对球状脂联素（gAD）进行了相同的研究。同时观察不同EAC细胞系中UHRF1 mRNA的表达。实时细胞分析（RTCA）用于检测细胞增殖，流式细胞术和倒置荧光显微镜用于检测细胞焦亡。进行生物信用分析以观察 UHRF1 与关键焦亡蛋白之间的相关性。使用OD值和CCK8测定来确定miR-378a-3p对EAC细胞的影响。采用实时定量聚合酶链反应和Western blot检测EAC细胞中UHRF1、gAD和miR-378a-3p之间的相关性。此外，还进行了体内和体外实验，检测抑制UHRF1表达后对肿瘤迁移和侵袭的相关影响。结果UHRF1与EAC患者的生存呈负相关，而miR-378a-3p则表现出相反的作用。此外，gAD 促进 EAC 细胞焦亡，上调 miR-378a-3p，并显着抑制 EAC 细胞的增殖。 gAD 通过上调 miR-378a-3p 直接降低 EAC 细胞中 UHRF1 的表达。在细胞迁移和侵袭实验中，抑制 UHRF1 表达可显着抑制 EAC 细胞转移。在动物实验中，我们再次证明gAD通过抑制UHRF1的表达诱导EAC细胞焦亡。结论gAD诱导的miR-378a-3p上调通过靶向UHRF1显着抑制EAC细胞的增殖。因此，gAD 可以作为化疗和放疗难治性 EAC 或具有相同焦亡作用机制的其他癌症的替代疗法。