title: MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene.
abstract: One of the hallmarks of malignancy is the polarization of tumor-associated macrophages (TAMs) from a pro-immune (M1-like) phenotype to an immune-suppressive (M2-like) phenotype. However, the molecular basis of the process is still unclear. MicroRNA (miRNA) comprises a group of small, non-coding RNAs that are broadly expressed by a variety of organisms and are involved in cell behaviors such as suppression or promotion of tumorigenesis. Here, we demonstrate that miR-19a-3p, broadly conserved among vertebrates, was downregulated in RAW264.7 macrophage cells of the M2 phenotype in conditoned medium of 4T1 mouse breast tumor cells. This downregulation correlated with an increased expression of the Fra-1 gene, which was reported to act as a pro-oncogene by supporting the invasion and progression of breast tumors. We found significant upregulation of miR-19a-3p in RAW264.7 macrophages after transfection with a miR-19a-3p mimic that resulted in a significant suppression of the expression of this gene. In addition, we could measure the activity of binding between miR-19a-3p and Fra-1 with a psiCHECK luciferase reporter system. Further, transfection of RAW264.7 macrophage cells with the miR-19a-3p mimic decreased the expression of the Fra-1 downstream genes VEGF, STAT3 and pSTAT3. Most importantly, the capacity of 4T1 breast tumor cells to migrate and invade was impaired in vivo by the intratumoral injection of miR-19a-3p. Taken together, these findings indicate that miR-19a-3p is capable of downregulating the M2 phenotype in M2 macrophages and that the low expression of this miRNA has an important role in the upregulation of Fra-1 expression and induction of M2 macrophage polarization.
authors.affiliation: 1] Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China [2] Department of Immunology, Nankai University, Tianjin, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Immunology, Nankai University, Tianjin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Si
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Chuang
authors.affiliation: Department of Immunology, Nankai University, Tianjin, China.
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gomez-Cabrero
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Reisfeld
authors.affiliation: Department of Immunology, Nankai University, Tianjin, China.
authors.forename: R
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D059016:Tumor Microenvironment; D020298:U937 Cells; D000099169:Fos-Related Antigen 1
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; C000715470:MAS1 protein, human; C549214:MIRN19A microRNA, human; C561642:MIRN19 microRNA, mouse