TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer

Xiang, Jinfeng; Hu, Qiangsheng; Qin, Yi; Ji, Shunrong; Xu, Wenyan; Liu, Wensheng; Shi, Si; Liang, Chen; Liu, Jiang; Meng, Qingcai; Liang, Dingkong; Ni, Quanxing; Xu, Jin; Zhang, Bo; Lei, Yu

doi:10.1038/s41419-018-0367-6

Cited by 41 publications

(28 citation statements)

References 41 publications

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“…Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4) plays a vital role in Wnt/β-catenin signaling pathway. It was identified as a transcriptional factor that was responsible for Egl-9 family hypoxia inducible factor 2 (EGLN2) silencing, which leads to upregulation of HIF-1α and finally affects glycolysis reprogramming [ 43 ]. There is a positive-feedback regulation between HIF-2α and β-catenin that HIF-2α/β-catenin complex could upregulate the activity of β-catenin and stabilize and increase transcriptional activity of HIF-2α.…”

Section: Introductionmentioning

confidence: 99%

Targeting hypoxic tumor microenvironment in pancreatic cancer

et al. 2021

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Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

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Section: Introductionmentioning

confidence: 99%

Targeting hypoxic tumor microenvironment in pancreatic cancer

et al. 2021

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“…Studies have also examined the role of glycolysis in prediction of patient survival. For example, higher TCF7L2 expression predicted worse prognosis in pancreatic cancer ( 19 ). Four glycolysis-related genes (GRGs) (AGRN, AKR1A1, DDIT4, and HMMR) were identified as closely related to the clinical outcome in patients with lung adenocarcinoma ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Glycolysis-Related Gene Signature for Predicting Breast Cancer Survival

et al. 2021

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To identify a glycolysis-related gene signature for the evaluation of prognosis in patients with breast cancer, we analyzed the data of a training set from TCGA database and four validation cohorts from the GEO and ICGC databases which included 1,632 patients with breast cancer. We conducted GSEA, univariate Cox regression, LASSO, and multiple Cox regression analysis. Finally, an 11-gene signature related to glycolysis for predicting survival in patients with breast cancer was developed. And Kaplan–Meier analysis and ROC analyses suggested that the signature showed a good prognostic ability for BC in the TCGA, ICGC, and GEO datasets. The analyses of univariate Cox regression and multivariate Cox regression revealed that it’s an important prognostic factor independent of multiple clinical features. Moreover, a prognostic nomogram, combining the gene signature and clinical characteristics of patients, was constructed. These findings provide insights into the identification of breast cancer patients with a poor prognosis.

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“…During Wnt activation, TCF7L2 was activated by Wnt ligands or certain growth factors (such as insulin and IGF-1), and further participated in many Wnt-related biological processes [6]. Previous study suggested that TCF7L2 may stimulate the proliferation of pancreatic β-cells and facilitate the production of the incretin hormone glucagon-like peptide-1 in intestinal endocrine cells [7–9], but the molecular mechanisms underlying are far from understood. TCF7L2 also plays an important role in conveying Wnt signaling pathway in regulating gene expression, and a highly significant proportion of genes bound by TCF7L2 are known disease-associated loci [10, 11].…”

Section: Introductionmentioning

confidence: 99%

TCF7L2 regulates pancreatic β-cell function through PI3K/AKT signal pathway

Wu¹,

Liu

et al. 2019

Diabetol Metab Syndr

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Background Transcription factor 7-like 2 (TCF7L2), which previously known as TCF-4, is a major form of transcription factor involved in the downstream WNT signaling and exhibits the strongest association to diabetes susceptibility. Although we still do not know mechanistically how TCF7L2 exerts its physiological functions on pancreatic endocrine cells, it had been suggested that TCF7L2 may directly affect β-cell function by regulating the activation of PI3K/AKT signaling pathway. Methods MIN6 cells were transfected with TCF7L2 knockdown virus or lenti-TCF7L2 virus for 48 h to evaluate the contribution of TCF7L2 to the PI3K/AKT signaling pathway and pancreatic β-cell function. This was confirmed by measuring the expression of PI3K p85 and p-Akt by western blotting and insulin secretion by enzyme-linked immunosorbent assay (ELISA), respectively. Chromatin immunoprecipitation (ChIP) and polymerase chain reaction (PCR) experiments were performed to explore the genomic distribution of TCF7L2-binding sites in the promoter of PIK3R1, the affinity between which was analyzed by the luciferase reporter assay. Results In the present study, we strikingly identified that TCF7L2 could profoundly inhibit the expression of PIK3R1 gene and its encoding protein PI3K p85, which then could lead to the activation of PI3K/AKT signaling and stimulate insulin secretion in pancreatic β-cells. However, the integrity and stability of evolutionarily conserved TCF7L2-binding motif plays a very crucial role in the binding events between transcription factor TCF7L2 and its candidate target genes. We also found that the affinity of TCF7L2 to the promoter region of PIK3R1 alters upon the specific binding sites, which further provides statistical validation to the necessity of TCF7L2-binding motif. Conclusions This study demonstrated that TCF7L2 is closely bound to the specific binding regions of PIK3R1 promoter and prominently controls the transcription of its encoding protein p85, which further affects the activation of PI3K/AKT signaling pathway and insulin secretion.

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TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer

Cited by 41 publications

References 41 publications

Targeting hypoxic tumor microenvironment in pancreatic cancer

Targeting hypoxic tumor microenvironment in pancreatic cancer

Identification of a Novel Glycolysis-Related Gene Signature for Predicting Breast Cancer Survival

TCF7L2 regulates pancreatic β-cell function through PI3K/AKT signal pathway

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