Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

• Published in: Oncogene Vol. 30; no. 41; pp. 4231 - 4242
• Main Authors: Musumeci, M, Coppola, V, Addario, A, Patrizii, M, Maugeri-Saccà, M, Memeo, L, Colarossi, C, Francescangeli, F, Biffoni, M, Collura, D, Giacobbe, A, D'Urso, L, Falchi, M, Venneri, M A, Muto, G, De Maria, R, Bonci, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.10.2011; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/327; 692/699/67/589/466; Aged; Aged, 80 and over; Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Cancer therapies; Care and treatment; Cell Biology; Cell Line, Tumor; Cell migration; Cell physiology; Cell proliferation; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Data processing; Development and progression; Down-Regulation; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; Fibroblast growth factor receptor 1; Fibroblast growth factors; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Gene silencing; Genetic aspects; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Invasiveness; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Microenvironments; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Molecular and cellular biology; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Nephrology. Urinary tract diseases; Oncology; original-article; Phosphorylation; Physiological aspects; Post-transcription; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; Stromal cells; Transplantation, Heterologous; Tumor cells; Tumor microenvironment; Tumor Microenvironment - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Italy; microenvironment; cancer progression; miRNA; Urinary system disease; RNA interference; Prostate disease; Micro RNA; Malignant tumor; Carcinogenesis; Gene silencing; Regulation(control); Tumor progression; Male genital diseases; Prostate cancer; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.140

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.