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

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.C-X3-C趋化因子受体1（CX3CR1）是一类重要的趋化因子受体，可调控胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）细胞的趋化迁移。截至目前，其调控机制仍未完全阐明。本研究发现，缺氧可上调胰腺癌细胞中CX3CR1的表达。在体内外实验中敲低缺氧诱导因子（hypoxia-inducible factor, HIF）-1α的表达后，CX3CR1的表达水平显著下调。染色质免疫沉淀实验证实，常氧条件下HIF-1α可结合CX3CR1启动子的缺氧反应元件（hypoxia-response element, HRE；5′-A/GCGTG-3′），且该结合作用在缺氧条件下显著增强。在胰腺癌细胞中，过表达HIF-1α可显著上调受CX3CR1启动子调控的荧光素酶报告基因的表达水平。尤为关键的是，本研究证实HIF-1α可通过CX3CR1调控癌细胞的迁移能力。HIF-1α/CX3CR1通路或可成为防治胰腺导管腺癌侵袭与远处转移的极具价值的治疗靶点。