title: MicroRNA-17, 20a regulates the proangiogenic function of tumor-associated macrophages via targeting hypoxia-inducible factor 2α.
abstract: Tumor-associated macrophages (TAMs) constitute a major component of the leukocyte infiltrate of most solid tumors, and they usually exhibit a proangiogenic phenotype which facilitates tumor growth in most circumstances. However, the precise mechanisms regulating the proangiogenic properties of TAMs remain largely unclear. In the present study, we found that the expression of hypoxia-inducible factor 2α (HIF-2α) was significantly up-regulated in macrophages from tumor tissues of several solid tumors. Macrophages exposed to tumor cell line derived-culture supernatants (TSN) also expressed high levels of HIF-2α in vitro, without a requirement for hypoxia. We identified miR-17 and miR-20a as the key regulators of HIF-2α expression in TAMs, and autocrine IL-6 played an important role in mediating the expression of miR-17, miR-20a, and thereafter HIF-2α in TAMs. Furthermore, the elevated HIF-2α in TAMs stimulated transcription of a set of proangiogenic genes such as VEGFA and PDGFB, which might in turn contribute to the angiogenic process within tumors. Our data provide evidence in support of the critical role of HIF-2α in the proangiogenic activity of TAMs and also reveal a novel mechanism by which miRNAs regulate TAM functions through modulation of HIF-2α expression under non-hypoxic conditions.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Zhenqun
authors.initials: Z
authors.lastname: Xu
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.forename: Ling-Yan
authors.initials: LY
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009841:Oligonucleotides / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015850:Interleukin-6; D035683:MicroRNAs; D009841:Oligonucleotides; D000099162:Endothelial PAS Domain-Containing Protein 1; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human