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

• Published in: PloS one Vol. 7; no. 8; p. e43399
• Main Authors: Zhao, Tiansuo, Gao, Song, Wang, Xiuchao, Liu, Jingcheng, Duan, Yitao, Yuan, Zhanna, Sheng, Jun, Li, Shasha, Wang, Feng, Yu, Ming, Ren, He, Hao, Jihui
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.08.2012; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adenocarcinoma - metabolism; Animals; Binding sites; Biology; Cancer; Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; Cell migration; Chemokines; Chemotaxis; Chromatin; Chromatin - metabolism; CX3C Chemokine Receptor 1; CX3CR1 protein; Disease prevention; Female; Flow Cytometry - methods; Gene expression; Gene Expression Regulation; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunoprecipitation; Laboratories; Ligands; Liver cancer; Medical prognosis; Medicine; Metastases; Mice; Mice, Nude; Microscopy, Confocal - methods; Neoplasm Metastasis; Pain; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Promoter Regions, Genetic; Proteins; Receptors, Chemokine - biosynthesis; Regulatory mechanisms (biology); Regulatory sequences; Reporter gene; RNA, Small Interfering - metabolism; Rodents; Transcription factors; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043399

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.