title: Hypoxia induces CXCR4 expression and biological activity in gastric             cancer cells through activation of hypoxia-inducible factor-1α.
abstract: Given the important role of CXCR4 in cancer metastasis, microenvironmental             factors that modulate CXCR4 may have an impact on the process of tumor expansion.             Hypoxia is a common feature of solid tumors and a significant microenvironmental             factor that drives aggressive behavior. CXCR4 is upregulated in several cancer             cells under hypoxic conditions, suggesting a relationship between tumor hypoxia             and CXCR4. However, the role of hypoxia in regulating CXCR4 in gastric cancer             remains poorly understood. KATO III gastric cancer cells were exposed to hypoxia             or normoxia. CXCR4 expression in cells transfected with shRNA specific for HIF-1α             was investigated by western blotting and flow cytometry. Wound healing, migration             and invasion assays were used to assess cell motility and the chemotactic response             to CXCL12, a major CXCR4 ligand. CXCR4 expression at the protein level and in             the cell membrane was significantly increased in KATO III cells following exposure             to hypoxia. This upregulation of CXCR4 was implicated in increased cell motility             and enhanced chemotactic responses (migration and invasion) to CXCL12 treatment             in vitro. The increases in CXCR4 expression and metastatic potential in gastric             cancer cells exposed to hypoxia were blocked by HIF-1α-specific shRNA. Our results             indicate that hypoxia upregulates CXCR4 in gastric cancer cells in a HIF-1α-dependent             manner, and that upregulation of CXCR4 plays a role in cancer cell migration and             invasion. Thus, disrupting the hypoxia-HIF-1α-CXCR4 axis could be an attractive             therapeutic strategy for the treatment of gastric cancer.
authors.affiliation: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-131, Republic of Korea.
authors.forename: Yoon Suk
authors.initials: YS
authors.lastname: Oh
authors.forename: Ha Yon
authors.initials: HY
authors.lastname: Kim
authors.forename: Ik-Chan
authors.initials: IC
authors.lastname: Song
authors.forename: Hwan-Jung
authors.initials: HJ
authors.lastname: Yun
authors.forename: Deog-Yeon
authors.initials: DY
authors.lastname: Jo
authors.forename: Samyong
authors.initials: S
authors.lastname: Kim
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D034622:RNA Interference; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D014945:Wound Healing / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4