Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
Cell Death Dis. 2018 Feb 23;9(3):321. doi: 10.1038/s41419-018-0367-6.
Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/β-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a β-catenin transcriptional partner, plays a vital role in the Wnt/β-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF-1α). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer.
胰腺导管腺癌患者的预后要差得多，人们已经投入大量精力来了解这种疾病的分子生物学方面。有大量证据表明，Wnt/β-catenin 信号的组成性激活有助于胰腺癌的发生和发展。转录因子 7 样 2/转录因子 4（TCF7L2/TCF4）是 β-catenin 的转录伴侣，在 Wnt/β-catenin 信号通路中发挥重要作用。在本研究中，我们研究了 TCF7L2 在胰腺癌中的临床病理意义。我们的结果表明，TCF7L2 表达水平较高的患者预后较差。我们的体外研究表明，TCF7L2 通过抑制 Egl-9 家族缺氧诱导因子 2（EGLN2）正向调节有氧糖酵解，导致缺氧诱导因子 1 ɑ 亚基（HIF-1α）上调。在胰腺癌患者和皮下异种移植小鼠模型中评估 FDG 摄取，进一步证实了 TCF7L2 对有氧糖酵解的影响。总之，我们确定了用于预后预测的新标志物，并提出 TCF7L2 在控制胰腺癌细胞有氧糖酵解中的先前未知作用。
