Hypoxia-Inducible Factor-1α Regulates Chemotactic Migration of Pancreatic Ductal Adenocarcinoma Cells through Directly Transactivating the CX3CR1 Gene

Zhao, Tiansuo; Gao, Song; Wang, Xiuchao; Liu, Jingcheng; Duan, Yitao; Yuan, Zhanna; Sheng, Jun; Li, Shasha; Wang, Feng; Yu, Ming; Ren, He; Hao, Jihui

doi:10.1371/journal.pone.0043399

Cited by 41 publications

(58 citation statements)

References 23 publications

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“…The mechanism responsible for receptor upregulation in tumors is unclear. CX 3 CR1 is not modulated in vitro by several cytokines (21), but recent studies suggested a role for hypoxia and NF-kB in receptor regulation in pancreatic cancer (47,48), a finding that we did not confirm (21) (and data not shown).…”

Section: Discussioncontrasting

confidence: 92%

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

Erreni

Siddiqui

Marelli

et al. 2016

The Journal of Immunology

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Human colorectal cancer (CRC) is a frequent neoplasia in Western countries, and its metastatic progression is a major cause of cancer-related death. In search of specific molecules upregulated in CRC, with possible clinical relevance, we performed a differential gene-profiling analysis in surgery-derived CRC samples and adjacent uninvolved intestinal mucosa. The chemokine CX3CL1 and its specific receptor CX3CR1 were significantly upregulated in tumors. Higher expression of CX3CL1 and CX3CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I–III). Unexpectedly, high immune scores of CX3CL1 did not correlate with the density of tumor-infiltrating CD3+ T cells or CD68+ macrophages. Coexpression of ligand and receptor by tumor cells (axis-positive tumors) significantly associated with longer disease-free (p = 0.01) and disease-specific survival (p = 0.001). Conversely, axis-negative tumors (with low expression of both ligand and receptor) had increased risk of tumor relapse (p = 0.02), and increased likelihood of metachronous metastasis (p = 0.001), including after stage adjustment (p = 0.006). Transduction of CX3CL1 and CX3CR1 in CRC tumor cell lines induced cell aggregation that strongly inhibited in vitro migration in chemotaxis assays. In a mouse model of spleen–liver metastases, cancer dissemination to liver was dramatically reduced in CX3CL1-CX3CR1–expressing tumors, and ligand–receptor interaction was confirmed in cancer cells in vivo by fluorescence resonance energy transfer analysis. In conclusion, tumoral expression of the CX3CL1-CX3CR1 chemokine axis functions as a retention factor, increasing homotypic cell adhesion and limiting tumor spreading to metastatic sites. Lack or low levels of expression of CX3CL1-CX3CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.

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Section: Discussioncontrasting

confidence: 92%

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

Erreni

Siddiqui

Marelli

et al. 2016

The Journal of Immunology

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“…siRNA against protein kinase C (PKC) was purchased from Santa Cruz Biotechnology (sc-29449). siRNAs against HIF-1a and pcDNA-HIF-1a plasmids were prepared as previously described (4,16). The fulllength fascin cDNA (GenBank no.6624) was ligated into expression vector pEGFP-C1 (Invitrogen) and verified by sequencing.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Hypoxia-inducible factor-1 (HIF-1; consists of highly regulated HIF-1a and a constitutively expressed HIF-1b) is the most important transcription factor as a result of intratumoral hypoxia, which can mediate many adaptive physiologic responses (3). In pancreatic cancer, HIF1a expression levels are associated with tumor progression, fibrotic focus, angiogenesis cell migration, and hepatic metastasis (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

et al. 2014

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Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1a expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1a and fascin in PDAC specimens, suggesting that hypoxia and HIF-1a were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1a knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression. Cancer Res; 74(9);

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“…A developing body of evidences has shown that hypoxia inducible factor-1α (HIF-1α) is involved in crucial aspects of cancer biology, including angiogenesis, proliferation, energy metabolism and invasion (Hiraki et al, 2012;Schito et al, 2012;Zhao et al, 2012;Cheng et al, 2013). Although the relevance of HIF-1α on the prognosis in NSCLC has been investigated, conflicting results have been reported from different laboratories (Volm et al, 2000;Hirami et al, 2004;Swinson et al, Wei Ping, Wen-Yang Jiang, Wen-Shu Chen, Wei Sun, Xiang-Ning Fu* Hung et al, 2009;Park et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Expression and Significance of Hypoxia Inducible Factor-1α and Lysyl Oxidase in Non-small Cell Lung Cancer

Wei

Jiang²,

Chen³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Hypoxia-Inducible Factor-1α Regulates Chemotactic Migration of Pancreatic Ductal Adenocarcinoma Cells through Directly Transactivating the CX3CR1 Gene

Cited by 41 publications

References 23 publications

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

Hypoxia-Inducible Factor-1 Promotes Pancreatic Ductal Adenocarcinoma Invasion and Metastasis by Activating Transcription of the Actin-Bundling Protein Fascin

Expression and Significance of Hypoxia Inducible Factor-1α and Lysyl Oxidase in Non-small Cell Lung Cancer

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