Abstract
CX3CR1 is an important chemokine receptor and regulates the chemotactic migration of pancreatic ductal adenocarcinoma (PDAC) cells. Up to now, its regulatory mechanism remains largely undefined. Here, we report that hypoxia upregulates the expression of CX3CR1 in pancreatic cancer cells. When hypoxia-inducible factor (HIF)-1α expression was knocked down in vitro and in vivo, the expression of CX3CR1 was significantly decreased. Chromatin immunoprecipitation assay demonstrated that HIF-1α bound to the hypoxia-response element (HRE; 5'-A/GCGTG-3') of CX3CR1 promoter under normoxia, and this binding was significantly enhanced under hypoxia. Overexpression of HIF-1α significantly upregulated the expression of luciferase reporter gene under the control of the CX3CR1 promoter in pancreatic cancer cells. Importantly, we demonstrated that HIF-1α may regulate cancer cell migration through CX3CR1. The HIF-1α/CX3CR1 pathway might represent a valuable therapeutic target to prevent invasion and distant metastasis in PDAC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism*
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Animals
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CX3C Chemokine Receptor 1
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Carcinoma, Pancreatic Ductal / metabolism*
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Cell Line, Tumor
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Chemotaxis
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Chromatin / metabolism
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Female
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Flow Cytometry / methods
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Gene Expression Regulation*
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Humans
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Hypoxia / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Ligands
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Mice
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Mice, Nude
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Microscopy, Confocal / methods
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Neoplasm Metastasis
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Pancreatic Neoplasms / metabolism*
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Promoter Regions, Genetic
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RNA, Small Interfering / metabolism
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Receptors, Chemokine / biosynthesis*
Substances
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CX3C Chemokine Receptor 1
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CX3CR1 protein, human
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Chromatin
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Cx3cr1 protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ligands
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RNA, Small Interfering
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Receptors, Chemokine
Grants and funding
This work was supported by grants from the National Natural Science Foundation of China (81172355 30973490, 30900596, 30901448), the New Century Excellent Talents Programme of the Ministry of Education (NCET-07-0614), the Natural Science Foundation of Tianjin (10JCZDJC20200) and the China Postdoctoral Science Foundation (20090450773). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.