title: Chemokine C-C motif receptor 5 and C-C motif ligand 5 promote cancer cell migration under hypoxia.
abstract: The chemokine CC motif receptor 5 (CCR5) and its ligands have been reported to be associated with cancer progression and metastasis. Although recent researches have demonstrated a fundamental role of hypoxia in cancer, the effect of hypoxia on the expression and function of CCR5 and its ligands in cancer cells is unknown. Here, we investigated the status of CCR5 and its ligands in cancer cells under hypoxic conditions. Quantitative polymerase chain reaction, western blotting and immunofluorescence staining showed that hypoxia induced a strong increase of CCR5 expression. Dual luciferase assay and mRNA stability analysis indicated that hypoxia-induced CCR5 mRNA expression relied on both transcriptional and posttranscriptional mechanisms. We detected the expression of CCR5 ligands and found that chemokine CC motif ligand 5 (CCL5) was induced under hypoxia. Recombinant human CCL5 stimulated cell migration rather than cell proliferation under hypoxia, and neutralization of CCL5 inhibited hypoxia-induced migration of cancer cells. Similarly, overexpression of CCR5 increased cell migration, and knockdown of CCR5 attenuated hypoxia-mediated cell migration. We further showed that hypoxia-inducible factor-1α (HIF-1α) was involved in CCR5 and CCL5 regulation under hypoxia. HIF-1α mRNA levels were highly correlated with CCR5 mRNA and CCL5 mRNA levels in clinical samples. CCR5 and CCL5 were highly expressed in breast cancer lymph nodes metastases. Taken together, our data suggest that CCR5-CCL5 interaction promotes cancer cell migration under hypoxia.
authors.affiliation: New Drug Screening Center, China Pharmaceutical University, Nanjing, China.
authors.forename: Sensen
authors.initials: S
authors.lastname: Lin
authors.forename: Shuying
authors.initials: S
authors.lastname: Wan
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Jialiang
authors.initials: J
authors.lastname: Hu
authors.forename: Dongdong
authors.initials: D
authors.lastname: Fang
authors.forename: Renping
authors.initials: R
authors.lastname: Zhao
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D018946:Chemokine CCL5 / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008207:Lymphatic Metastasis; D008875:Middle Aged; D034622:RNA Interference; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D018946:Chemokine CCL5; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019713:Receptors, CCR5