Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: A meta-analysis

Ye, Long‐Yun; Zhang, Qi; Bai, Xueli; Prasoon, Pankaj; Hu, Qi-Da

doi:10.1016/j.pan.2014.06.008

Cited by 58 publications

(51 citation statements)

References 18 publications

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“…This observation correlates with a significant reduction in VEGF-A which is involved in the recruitment of stromal cells. Similar to AKT, HIF-1α expression has been associated with poor prognosis and early recurrence in PDAC [35]. Hypoxic zones with subsequent stabilization of HIF-1 are very common in PDAC [26, 33, 35].…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models

et al. 2017

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Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro. Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1α (HIF-1α) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.

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Section: Discussionmentioning

confidence: 99%

“…Similar to AKT, HIF-1α expression has been associated with poor prognosis and early recurrence in PDAC [35]. Hypoxic zones with subsequent stabilization of HIF-1 are very common in PDAC [26, 33, 35]. In the context of hypoxia, we and others have described HIF-1α inhibition upon targeting mTORC1 with rapamycin [36–38].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models

et al. 2017

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“…In addition to the adverse consequences of elevated VEGF-A levels in pancreatic cancer, abundant expression of HIF-1α contributes substantially to the pathophysiology of this disease [57, 58]. We found that under normoxic tissue culture conditions increased HIF-1α expression in PDAC cell lines was associated with DUOX2-related H 2 O 2 production and ERK activation following exposure to IFN-γ, and that these results could be mimicked by the short-term exposure of PDAC cells to concentrations of exogenous H 2 O 2 as low as 1 μM (Figure 3C).…”

Section: Discussionmentioning

confidence: 99%

Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1α and VEGF-A

Meitzler

Antony

et al. 2016

Oncotarget

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Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-γ treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-γ-induced VEGF-A or HIF-1α up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human pre-malignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas.

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“…Overexpression of hif-1α correlates with lymph node metastasis and poor prognosis in patients with pancreatic cancer [7]. However, studies suggested that hif-1α is mainly induced in severe hypoxia to help cells resist temporary stress [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducible factor-2α promotes tumor progression and has crosstalk with Wnt/β-catenin signaling in pancreatic cancer

et al. 2017

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BackgroundPancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood.MethodsHerein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function. Using several cell lines, mouse models, and human tissues, we obtained a general picture of hif-2α in pancreatic cancer progression.ResultsFunctional assays revealed that hif-2α promotes epithelial-to-mesenchymal transition, enhances tumor proliferation and invasion, increases stemness, facilitates angiogenesis, and up-regulates aerobic glycolysis. We identified an interaction between hif-2α and β-catenin, and found that hif-2α/β-catenin complex formation increased the activity of β-catenin and the protein stability of hif-2α. In vivo study confirmed the pro-oncogenic role of hif-2α, whose expression correlated with those of E-cadherin, vimentin, Ki-67, and CD31, but not hif-1α. A human tissue study showed that hif-2α was associated with lymph node metastasis, pathological grade, stroma abundance, vascularization and patient survival. High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer.ConclusionsOur systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.

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Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: A meta-analysis

Cited by 58 publications

References 18 publications

Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models

Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models

Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1α and VEGF-A

Hypoxia-inducible factor-2α promotes tumor progression and has crosstalk with Wnt/β-catenin signaling in pancreatic cancer

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