Abstract
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 18FDG 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases, with remarkably highly lethality rates
To explore the impact of TCF7L2 on pancreatic cancer patient prognosis, we examined the expression of TCF7L2 in the Cancer Genome Atlas (TCGA) pancreatic cancer patients
These results demonstrated that TCF7L2 expression was significantly related to the overall survival (OS) of pancreatic cancer patients (Fig. 1b)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases, with remarkably highly lethality rates. Official journal of the Cell Death Differentiation Association. Xiang et al Cell Death and Disease (2018)9:321. The hypoxic adaption mediated by the master transcriptional regulator, HIF-1α, is the best characterized metabolic alteration, which mediates the survival of tumour cells to survive by aerobic glycolysis reprogramming[10]. This process is known as the “Warburg effect”, in which glucose is metabolized through glycolysis to generate ATP and basic raw materials for biosynthesis[11,12]. HIF-1α-mediated metabolic reprogramming creates a specific matrix with suitable acid-base characteristics and promotes angiogenesis for invasion and metastasis, which correlates closely with resistance to chemotherapy and radiotherapy and may serve as a treatment target[13]
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