title: Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer.
abstract: The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Musumeci
authors.forename: V
authors.initials: V
authors.lastname: Coppola
authors.forename: A
authors.initials: A
authors.lastname: Addario
authors.forename: M
authors.initials: M
authors.lastname: Patrizii
authors.forename: M
authors.initials: M
authors.lastname: Maugeri-Saccà
authors.forename: L
authors.initials: L
authors.lastname: Memeo
authors.forename: C
authors.initials: C
authors.lastname: Colarossi
authors.forename: F
authors.initials: F
authors.lastname: Francescangeli
authors.forename: M
authors.initials: M
authors.lastname: Biffoni
authors.forename: D
authors.initials: D
authors.lastname: Collura
authors.forename: A
authors.initials: A
authors.lastname: Giacobbe
authors.forename: L
authors.initials: L
authors.lastname: D'Urso
authors.forename: M
authors.initials: M
authors.lastname: Falchi
authors.forename: M A
authors.initials: MA
authors.lastname: Venneri
authors.forename: G
authors.initials: G
authors.lastname: Muto
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.forename: D
authors.initials: D
authors.lastname: Bonci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt