MicroRNA miR-199a-3p regulates cell proliferation and survival by targeting caveolin-2

Recent advances in the study of microRNAs indicate that they have an important role in regulating cellular activities such as proliferation, morphogenesis, apoptosis and differentiation by regulating the expression of various genes. MiR-199a-3p is highly expressed in hair follicles and in some tumor cells, suggesting its participation in tumor progression, but it is significantly underexpressed in hepatocellular carcinoma and in bladder cancer. The mechanism underlying these effects is not yet known. Here, we dissect the effects of miR-199a-3p on YPEN-1 endothelial cells, and MDA-MB-231 and MT-1 breast cancer cell lines. We found that expression of miR-199a-3p promotes proliferation and survival of endothelial cells as well as breast cancer cells. Remarkably, miR-199a-3p inhibited both endogenous caveolin-2 activity and exogenous caveolin-2 activity, which was confirmed by a reporter construct bearing the 3′-untranslated region of caveolin-2. However, overexpression of caveolin-2 completely counteracted the enhancement of miR-199a-3p-mediated activities on cell proliferation, survival and sensitivity of tumor cells to anticancer drugs. Our findings suggest that MiR-199a-3p targeting of caveolin-2 might have an important role in breast cancer tumor progression, making it a potential candidate for intervention in cancer.

[1]  W. Choi,et al.  Caveolin-2 regulation of STAT3 transcriptional activation in response to insulin. , 2009, Biochimica et biophysica acta.

[2]  K. Mimori,et al.  Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer , 2004, British Journal of Cancer.

[3]  R. Stallings,et al.  Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. , 2007, Cancer research.

[4]  Ole A. Andreassen,et al.  Brain Expressed microRNAs Implicated in Schizophrenia Etiology , 2007, PloS one.

[5]  Sangmin Kim,et al.  Caveolin-2 regulation of the cell cycle in response to insulin in Hirc-B fibroblast cells. , 2005, Biochemical and biophysical research communications.

[6]  W. Krajewska,et al.  Caveolins: structure and function in signal transduction. , 2004, Cellular & molecular biology letters.

[7]  Michael Zuker,et al.  MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression , 2004, Nature Genetics.

[8]  I. Ellis,et al.  CAV1 and CAV2 are associated with breast cancer basal-like and triple negative immunophenotype , 2008 .

[9]  M. Lisanti,et al.  Expression of caveolin-1 and caveolin-2 in urothelial carcinoma of the urinary bladder correlates with tumor grade and squamous differentiation. , 2003, American journal of clinical pathology.

[10]  I. Ellis,et al.  Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype , 2008, British Journal of Cancer.

[11]  L. Brunton,et al.  Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. , 2001, Annual review of pharmacology and toxicology.

[12]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[13]  Yaou Zhang,et al.  MicroRNA miR-328 Regulates Zonation Morphogenesis by Targeting CD44 Expression , 2008, PloS one.

[14]  Martina Paulsen,et al.  Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene , 2003, Nature Genetics.

[15]  R. Parton,et al.  Lipid Rafts and Caveolae as Portals for Endocytosis: New Insights and Common Mechanisms , 2003, Traffic.

[16]  R. Chen,et al.  Regulation of IKKβ by miR-199a affects NF-κB activity in ovarian cancer cells , 2008, Oncogene.

[17]  P. Fumoleau,et al.  A multicentre phase II study of the efficacy and safety of docetaxel as first-line treatment of advanced breast cancer: report of the Clinical Screening Group of the EORTC. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[18]  Robin L. Jones,et al.  Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients , 2008, Breast Cancer Research and Treatment.

[19]  C. Mello,et al.  Micromanaging insulin secretion , 2004, Nature Medicine.

[20]  M. Kattan,et al.  Elevated expression of caveolin is associated with prostate and breast cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  Ling Fang,et al.  Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis , 2010, Nucleic acids research.

[22]  R. Parton,et al.  Caveolin-3 Associates with Developing T-tubules during Muscle Differentiation , 1997, The Journal of cell biology.

[23]  T. Tuschl,et al.  New microRNAs from mouse and human. , 2003, RNA.

[24]  C. Croce,et al.  MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. , 2010, Cancer research.

[25]  M. Lisanti,et al.  The Caveolin genes: from cell biology to medicine , 2004, Annals of medicine.

[26]  N. Rajewsky,et al.  A pancreatic islet-specific microRNA regulates insulin secretion , 2004, Nature.

[27]  I. Fichtner,et al.  Characterization of two human mammary carcinomas, MT-1 and MT-3, suitable forin vivo testing of ether lipids and their derivatives , 2005, Breast Cancer Research and Treatment.

[28]  Ji Young Kim,et al.  MicroRNA miR-199a* Regulates the MET Proto-oncogene and the Downstream Extracellular Signal-regulated Kinase 2 (ERK2)* , 2008, Journal of Biological Chemistry.

[29]  W. B. Derry,et al.  Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. , 1996, Cancer research.

[30]  Phillip A. Sharp,et al.  miRNA Profiling of Naïve, Effector and Memory CD8 T Cells , 2007, PloS one.

[31]  Chang-Zheng Chen,et al.  MicroRNAs as oncogenes and tumor suppressors. , 2005, The New England journal of medicine.

[32]  Yong Zhao,et al.  Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis , 2005, Nature.

[33]  G. Tsujimoto,et al.  Identification of novel microRNA targets based on microRNA signatures in bladder cancer , 2009, International journal of cancer.

[34]  Richard G. W. Anderson,et al.  Dual control of caveolar membrane traffic by microtubules and the actin cytoskeleton , 2002, Journal of Cell Science.

[35]  Burton B. Yang,et al.  MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression , 2007, Proceedings of the National Academy of Sciences.

[36]  Yaou Zhang,et al.  MicroRNA miR-378 Regulates Nephronectin Expression Modulating Osteoblast Differentiation by Targeting GalNT-7 , 2009, PloS one.

[37]  Xin Li,et al.  A microRNA Mediates EGF Receptor Signaling and Promotes Photoreceptor Differentiation in the Drosophila Eye , 2005, Cell.

[38]  H. Horvitz,et al.  MicroRNA Expression in Zebrafish Embryonic Development , 2005, Science.

[39]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[40]  C. Burge,et al.  The microRNAs of Caenorhabditis elegans. , 2003, Genes & development.

[41]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[42]  E. Sontheimer,et al.  Distinct Roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA Silencing Pathways , 2004, Cell.

[43]  Burton B. Yang,et al.  A 3′-Untranslated Region (3′UTR) Induces Organ Adhesion by Regulating miR-199a* Functions , 2009, PloS one.

[44]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[45]  S. Merajver,et al.  Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer , 2006, Breast Cancer Research and Treatment.

[46]  Y. Fujii,et al.  The overexpression of caveolin-1 and caveolin-2 correlates with a poor prognosis and tumor progression in esophageal squamous cell carcinoma. , 2007, Oncology reports.

[47]  Richard G. W. Anderson,et al.  Function of Caveolae in Ca2+ Entry and Ca2+‐Dependent Signal Transduction , 2003, Traffic.

[48]  G. Fiucci,et al.  Up-regulation of Caveolae and Caveolar Constituents in Multidrug-resistant Cancer Cells* , 1998, The Journal of Biological Chemistry.

[49]  Annick Harel-Bellan,et al.  The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation , 2006, Nature Cell Biology.

[50]  Angela K Nevins,et al.  Caveolin-1 Functions as a Novel Cdc42 Guanine Nucleotide Dissociation Inhibitor in Pancreatic β-Cells* , 2006, Journal of Biological Chemistry.

[51]  Jie Yang,et al.  MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8 , 2011, Oncogene.

[52]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[53]  Wei Wang,et al.  MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. , 2007, Cancer research.

[54]  F. Dietrich,et al.  Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs , 2006, Nature Genetics.

[55]  R. Russell,et al.  bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila , 2003, Cell.

[56]  T. Okanoue,et al.  Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues , 2006, Oncogene.

[57]  A. Hall,et al.  Rho GTPases and their effector proteins. , 2000, The Biochemical journal.

[58]  Eeva Kettunen,et al.  Caveolins as tumour markers in lung cancer detected by combined use of cDNA and tissue microarrays , 2004, The Journal of pathology.

[59]  Yaou Zhang,et al.  MicroRNA MiR-17 retards tissue growth and represses fibronectin expression , 2009, Nature Cell Biology.

[60]  Hanah Margalit,et al.  Host Immune System Gene Targeting by a Viral miRNA , 2007, Science.

[61]  Robin L. Jones,et al.  Distribution and significance of caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis , 2008, Breast Cancer Research and Treatment.