Globular adiponectin induces esophageal adenocarcinoma cell pyroptosis via the miR-378a-3p/UHRF1 axis.

ABSTRACT

BACKGROUND: Antiapoptosis 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). METHODS: Differential 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. RESULTS: UHRF1 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. CONCLUSION: gAD-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.