Zhang Jingbo, Kuang Lei, Li Yanyu, Wang Qing, Xu Hui, Liu Jianwei, Zhou Xueyan, Li Yang, Zhang Bei
Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Front Oncol. 2022 Apr 11;12:856707. doi: 10.3389/fonc.2022.856707. eCollection 2022.
To investigate the relationship between TET2 expression and endometrial cancer's clinicopathological features and prognosis, and the effect of metformin on TET2 and 5hmC levels in endometrial cancer cells.
The clinical significance of TET2 expression in endometrial carcinoma was analyzed from TCGA public database. Eighty-eight patients with endometrial cancer and 20 patients with normal proliferative endometrium were enrolled in this study. TET2 and 5hmC were respectively detected by Immunohistochemistry and ELISA in endometrial tissues. Kaplan-Meier and Cox proportional hazard regression models were used to analyze relationships between TET2 and 5hmC and the overall survival of EC patients. Endometrial cell proliferation was assessed after TET2 gene knockdown. Western blotting and real-time PCR were used to detect the effect of metformin on TET2 expression and to explore whether AMPK is involved in metformin-mediated TET2 regulation.
The clinical significance of expression of TET2 in endometrial cancer from TCGA public database confirmed that TET2 expression was significantly down-regulated in cancer samples and TET2 expression was also significantly different among different histopathological samples and TET2 is down-regulated in advanced, high-grade, and relapsed endometrial carcinoma tissues(P<0.05). Immunohistochemical analysis showed that TET2 and 5hmC levels were significantly lower in endometrial adenocarcinoma(P<0.05). TET2 expression was correlated with the degree of EC differentiation (P < 0.05). 5hmC levels were associated with clinical stage, differentiation, the depth of myometrial invasion, and lymph node metastasis (P < 0.05). The mean survival time of patients with negative staining for TET2 and 5hmC was shorter than that of patients with positive staining for both markers (P<0.05). Multivariate Cox regression analysis showed that TET2 expression was an independent risk factor for prognosis in patients with endometrial adenocarcinoma (HR = 14.520, 95% CI was 1.From 060 to 198.843, P = 0.045). siRNA-mediated TET2 knockdown increased the proliferation of EC cells. Metformin increased the levels of TET2 and 5hmC in EC cells. AMPK was involved in the regulation of TET2 by metformin.
TET2 may play an important role in EC development and may be a prognostic marker. Moreover, TET2 may be involved in a novel mechanism by which metformin inhibits EC cell proliferation.
探讨TET2表达与子宫内膜癌临床病理特征及预后的关系，以及二甲双胍对子宫内膜癌细胞中TET2和5hmC水平的影响。
从TCGA公共数据库分析TET2表达在子宫内膜癌中的临床意义。本研究纳入88例子宫内膜癌患者和20例正常增殖期子宫内膜患者。采用免疫组织化学和ELISA法分别检测子宫内膜组织中的TET2和5hmC。采用Kaplan-Meier法和Cox比例风险回归模型分析TET2和5hmC与子宫内膜癌患者总生存的关系。在TET2基因敲低后评估子宫内膜细胞增殖情况。采用蛋白质免疫印迹法和实时荧光定量PCR检测二甲双胍对TET2表达的影响，并探讨AMPK是否参与二甲双胍介导的TET2调控。
TCGA公共数据库中子宫内膜癌TET2表达的临床意义证实，癌组织样本中TET2表达显著下调，不同组织病理学样本中TET2表达也有显著差异，且在晚期、高级别和复发性子宫内膜癌组织中TET2表达下调（P<0.05）。免疫组织化学分析显示，子宫内膜腺癌中TET2和5hmC水平显著降低（P<0.05）。TET2表达与子宫内膜癌分化程度相关（P<0.05）。5hmC水平与临床分期、分化程度、肌层浸润深度和淋巴结转移相关（P<0.05）。TET2和5hmC染色均为阴性的患者平均生存时间短于两种标志物染色均为阳性的患者（P<0.05）。多因素Cox回归分析显示，TET2表达是子宫内膜腺癌患者预后的独立危险因素（HR=14.520，95%CI为1.060至198.843，P=0.045）。siRNA介导的TET2敲低增加了子宫内膜癌细胞的增殖。二甲双胍增加了子宫内膜癌细胞中TET2和5hmC的水平。AMPK参与了二甲双胍对TET2的调控。
TET2可能在子宫内膜癌发生发展中起重要作用，可能是一种预后标志物。此外，TET2可能参与了二甲双胍抑制子宫内膜癌细胞增殖的新机制。
