Nuclear Factor-κB–Dependent Epithelial to Mesenchymal Transition Induced by HIF-1α Activation in Pancreatic Cancer Cells under Hypoxic Conditions

Cheng, Zhuoxin; Sun, Bei; Wang, Shuangjia; Gao, Yue; Zhang, Yingmei; Zhou, Haoxin; Chen, Zhangjian; Wang, Yongwei; Kong, Rui; Pan, Shangha; Xue, Dongbo; Jiang, Hongchi; Bai, Xuewei

doi:10.1371/journal.pone.0023752

Cited by 92 publications

(60 citation statements)

References 31 publications

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“…GLI1 knockdown by RNA interference restrains cell invasion and EMT in HCC [31]. Moreover, some studies recently showed that numerous molecular signaling pathways, containing Hh pathway [32], could be activated under hypoxia conditions [33, 34]. However, the function of Hh pathway involved in the hypoxia-driven EMT and metastasis of HCC cells together with its relation with HIF-1α-induced ROS remain unclarified.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Liu¹,

Tu²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated. Methods: HCC cells were cultured under controlled hypoxia conditions or normoxic conditions. Transwell assays were used to examine the migration and invasion capacity. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. Results: In present study, we first observed a strongly positive correlation between HIF-1α and GLI1 expression in HCC tissues. Then, we showed that hypoxia significantly promoted EMT process and invasion of HCC cells, associated with activating the non-canonical Hh pathway without affecting SHH and PTCH1 expression. HIF-1α knockdown mitigated hypoxia-induced SMO and GLI1 expression, EMT invasion of HCC cells. Moreover, the SMO inhibitor or GLI1 siRNA also reversed the hypoxia-driven EMT and invasion of HCC cells under hypoxia condition. Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in HCC cells. In addition, we found that hypoxia increased ROS production and that ROS inhibitors (NAC) blocked GLI1-dependent EMT process and invasion under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is involved in hypoxia-induced ROS production. NOX4 expression was found to be increased at both mRNA and protein levels in hypoxic HCC cells. Furthermore, siRNA-mediated knockdown of NOX4 expression abolished hypoxia induced ROS generation and GLI1-dependent activation and invasion of HCC cells. Conclusion: Our findings indicate that hypoxia triggers ROS-mediated GLI1-dependent EMT progress and invasion of HCC cells through induction of NOX4 expression. Thus, hypoxia-driven ROS mediated non-canonical Hh signaling may play an important role in the initiation of EMT and provides a potential marker for cancer prevention and treatment.

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Section: Introductionmentioning

confidence: 99%

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Liu¹,

Tu²,

Wang³

et al. 2017

Cell Physiol Biochem

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“…The methodology has been described previously (41). In brief, BxPC-3 cells were seeded in 6-well plates and incubated for 24 hours at 37 C. The cells were then transfected with NF-kB p65 cDNA, control empty vector (pcDNA3.0), NF-kB p65 siRNA and control siRNA, respectively, using Lipofectamine 2000 (Invitrogen).…”

Section: Plasmids and Transfectionsmentioning

confidence: 99%

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Wang

Zhou

et al. 2016

Cancer Prevention Research

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Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-kB, and suppressed the NF-kB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-kB-and NF-kB-regulated gene products.Cancer Prev Res; 9(3); 234-44. Ó2015 AACR.

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“…It has be further investigated to what extent HIF--1α and PDGF--A are coexpressed in pancreatic cancer [88]. Recent data show a correlation between hypoxic environment, induced HIF--1α expression and pancreatic cancer cells resistance to gemcitabine [89]; furthermore HIF--1α overexpression seems promote EMT and facilitate invasiveness of pancreatic cancer cells [90,91].…”

Section: Novel Molecular Targets: Hif and Angiogenesismentioning

confidence: 99%

Molecular and Genetic Bases of Pancreatic Cancer

Vaccaro¹,

Bria

Iapicca

et al. 2012

CDT

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This is an author version of the contribution published on:Questa è la versione dell'autore dell'opera: Vaccaro V. et This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo--proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial--to--mesenchymal transition and its influence on sensitivity to EGFR--targeted approaches, apoptotic pathways, hypoxia--related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically.Introduction.

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Nuclear Factor-κB–Dependent Epithelial to Mesenchymal Transition Induced by HIF-1α Activation in Pancreatic Cancer Cells under Hypoxic Conditions

Cited by 92 publications

References 31 publications

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Molecular and Genetic Bases of Pancreatic Cancer

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