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.
Highlights
CX3CR1 is normally expressed by hematopoetic cells [1], prostate cancer [2], breast cancer [3] and pancreatic ductal adenocarcinoma (PDAC) [4]
Since hypoxia is a common feature of the microenvironment of solid tumors, it is important to detect whether hypoxia promotes the expression of CX3CR1 in pancreatic cancer cells
We have confirmed that CX3CR1 was highly expressed in both clinical samples and cell lines of pancreatic cancer and that hypoxia induced the expression of CX3CR1
Summary
CX3CR1 is normally expressed by hematopoetic cells [1], prostate cancer [2], breast cancer [3] and pancreatic ductal adenocarcinoma (PDAC) [4]. CX3CL1 is defined as a membrane as well as a soluble chemokine expressed by neurons and activated endothelial cells [7,8]. Recent evidence has shown that the CX3CL1/CX3CR1 pair plays a major role in adhesion, migration and survival of tumor cells including pancreatic cancer cells [4]. It is well known that tumor neurotropism is a major cause of recurrence after curative resection in PDAC [11]. The role of CX3CR1 in the neurotropism of pancreatic cancer has been established, the regulatory mechanism of this chemotactic migration remains to be elucidated
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