FOXA2 抑制 PKM2 转录并影响 Wnt/β-catenin 活性以阻断甲状腺癌中的有氧糖酵解,Clinical and Experimental Pharmacology and Physiology

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FOXA2 抑制 PKM2 转录并影响 Wnt/β-catenin 活性以阻断甲状腺癌中的有氧糖酵解
Clinical and Experimental Pharmacology and Physiology ( IF 2.4 ) Pub Date : 2023-03-22 , DOI: 10.1111/1440-1681.13773
Yawei He ₁ , Wanjing Chen ₁ , Liang Yu ₁ , Yanwei Liu ₁ , Yunsheng Cheng ₁ , Xianghua Li ₂ , Gang Yu ₁

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有氧糖酵解对癌细胞的能量代谢至关重要。本研究重点关注叉头盒 A2 (FOXA2) 对丙酮酸激酶 M2 (PKM2) 的调控及其对甲状腺癌 (THCA) 细胞糖酵解活性和恶性表型的影响。通过分析四个 Gene Expression Omnibus 数据集和查询生物信息学系统，我们获得了 FOXA2 作为 THCA 中表达不良的转录因子。后来，我们通过定量聚合酶链反应和蛋白质印迹分析验证了 THCA 细胞中 FOXA2 的 mRNA 和蛋白质水平降低。THCA细胞中FOXA2的上调抑制了葡萄糖的摄取和乳酸的产生，降低了细胞外酸化率，但增加了细胞的耗氧率。同时，FOXA2 过表达阻断了增殖和迁移，和癌细胞的致瘤活性。染色质免疫沉淀和荧光素酶测定显示 FOXA2 与 PKM2 启动子结合并抑制 PKM2 的转录，PKM2 在 THCA 细胞中高表达。PKM2 的进一步上调提高了 β-连环蛋白、c-Myc 和细胞周期蛋白 D1 的水平，并恢复了糖酵解活性以及癌细胞的恶性特性。总的来说，这项工作表明 FOXA2 通过阻断 PKM2 转录和灭活 Wnt/β-catenin 通路来抑制有氧糖酵解和 THCA 的进展。c-Myc 和细胞周期蛋白 D1 水平并恢复糖酵解活性以及癌细胞的恶性特性。总的来说，这项工作表明 FOXA2 通过阻断 PKM2 转录和灭活 Wnt/β-catenin 通路来抑制有氧糖酵解和 THCA 的进展。c-Myc 和细胞周期蛋白 D1 水平并恢复糖酵解活性以及癌细胞的恶性特性。总的来说，这项工作表明 FOXA2 通过阻断 PKM2 转录和灭活 Wnt/β-catenin 通路来抑制有氧糖酵解和 THCA 的进展。

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FOXA2 suppresses PKM2 transcription and affects the Wnt/β-catenin activity to block aerobic glycolysis in thyroid carcinoma

Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.

更新日期：2023-03-22

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