Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, 0608638, Japan.
Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
J Exp Clin Cancer Res. 2021 Jun 26;40(1):216. doi: 10.1186/s13046-021-02018-1.
Epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis. Although increasing evidence demonstrates an association between EMT induction and enhanced aerobic glycolysis in human cancer, the mechanisms linking these two conditions in endometrial cancer (EC) cells remain poorly defined.
We characterized the role and molecular mechanism of the glycolytic enzyme hexokinase 2 (HK2) in mediating EMT and glycolysis and investigated how long noncoding RNA DLEU2 contributes to the stimulation of EMT and glycolysis via upregulation of HK2 expression.
HK2 was highly expressed in EC tissues, and its expression was associated with poor overall survival. Overexpression of HK2 effectively promoted EMT phenotypes and enhanced aerobic glycolysis in EC cells via activating FAK and its downstream ERK1/2 signaling. Moreover, microRNA-455 (miR-455) served as a tumor suppressor by directly interacting with HK2 mRNA and inhibiting its expression. Furthermore, DLEU2 displayed a significantly higher expression in EC tissues, and increased DLEU2 expression was correlated with worse overall survival. DLEU2 acted as an upstream activator for HK2-induced EMT and glycolysis in EC cells through two distinct mechanisms: (i) DLEU2 induced HK2 expression by competitively binding with miR-455, and (ii) DLEU2 also interacted with EZH2 to silence a direct inhibitor of HK2, miR-181a.
This study identified DLEU2 as an upstream activator of HK2-driven EMT and glycolysis in EC cells and provided significant mechanistic insights for the potential treatment of EC.
上皮间质转化（EMT）和有氧糖酵解是癌症转移中涉及的基本过程。尽管越来越多的证据表明 EMT 诱导与人类癌症中增强的有氧糖酵解之间存在关联，但在子宫内膜癌（EC）细胞中，将这两种情况联系起来的机制仍未得到明确界定。
我们描述了糖酵解酶己糖激酶 2（HK2）在介导 EMT 和糖酵解中的作用和分子机制，并研究了长链非编码 RNA DLEU2 如何通过上调 HK2 表达来促进 EMT 和糖酵解。
HK2 在 EC 组织中高表达，其表达与总体生存不良相关。HK2 的过表达通过激活 FAK 及其下游 ERK1/2 信号有效地促进了 EC 细胞的 EMT 表型和有氧糖酵解。此外，miR-455（miR-455）作为一种肿瘤抑制因子，通过直接与 HK2 mRNA 相互作用并抑制其表达。此外，DLEU2 在 EC 组织中表达明显升高，增加的 DLEU2 表达与总体生存不良相关。DLEU2 通过两种不同的机制作为 HK2 诱导的 EMT 和糖酵解在 EC 细胞中的上游激活剂：（i）DLEU2 通过竞争性结合 miR-455 诱导 HK2 表达，和（ii）DLEU2 还与 EZH2 相互作用，沉默 HK2 的直接抑制剂 miR-181a。
本研究确定 DLEU2 为 EC 细胞中 HK2 驱动的 EMT 和糖酵解的上游激活剂，并为 EC 的潜在治疗提供了重要的机制见解。
