MiR-296 regulation of a cell polarity-cell plasticity module controls tumor progression

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Oncogene (Impact Factor: 8.46). 06/2011; 31(1):27-38. DOI: 10.1038/onc.2011.209
Source: PubMed


The expression of small, non-coding RNA, or microRNAs (miR), is frequently deregulated in human cancer, but how these pathways affect disease progression is still largely elusive. Here, we report on a microRNA, miR-296, which is progressively lost during tumor progression, and correlates with metastatic disease in colorectal, breast, lung, gastric, parathyroid, liver and bile ducts cancers. Functionally, miR-296 controls a global cell motility gene signature in epithelial cells by transcriptionally repressing the cell polarity-cell plasticity module, Scrib. In turn, loss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration, and tumor cell invasiveness. Re-expression of miR-296 in MDA-MB231 cells inhibits tumor growth, in vivo. Finally, miR-296 or Scrib levels predict tumor relapse in hepatocellular carcinoma patients.
These data identify miR-296 as a global repressor of tumorigenicity, and uncover a previously unexplored exploitation of Scrib in tumor progression in humans.

Download full-text


Available from: Valentina Vaira,
  • Source
    • "Of the 375 miRNAs assayed by TaqMan miRNA Array, 125 showed enrichment in the renal stroma and its derivatives based on C T cutoff value of <30 (Fig. 7A) (Table S3). These miRNAs included several miRNAs involved in vascular development (miRs-34a, 126, 145, 296-5p 302a, and 320) (Jeyaseelan et al. 2008; Cordes et al. 2009; Larsson et al. 2009; Liu et al. 2009; Pang et al. 2010; Vaira et al. 2012), members of the miR-17~92 cluster (miRs-17, 19a, 19b, 20a, 20b, 92a), and apoptosis-related miRNAs (miRs-10a, 17 and 106) (Ho et al. 2011) (Fig. 7B). To validate the miRNA profiling data, we performed locked nucleic acid section in situ hybridization (LNA-SISH) and corroborated the expression for miRs-320a, 34a, 126, and 145 (Fig. 7C). "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1(GC);Dicer(fl/fl) transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1(+) stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1(+)-derived cells and mRNA profiling of differentially expressed transcripts in FoxD1(GC);Dicer(fl/fl) kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development.
    10/2015; 3(10). DOI:10.14814/phy2.12537
  • Source
    • "Each step was performed at room temperature. Neoplastic lesions were isolated and separated from the normal lung tissue using the LMD 6000 system (Leica Microsystems), as previously described [23]. Microdissected samples were collected into the cap of 0.2-ml microcentrifuge tubes and stored at 4°C. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The recent introduction of pathology tissue-chromatin immunoprecipitation (PAT-ChIP), a technique allowing chromatin immunoprecipitation from formalin-fixed and paraffin-embedded (FFPE) tissues, has expanded the application potential of epigenetic studies in tissue samples. However, FFPE tissue section analysis is strongly limited by tissue heterogeneity, which hinders linking the observed epigenetic events to the corresponding cellular population. Thus, ideally, to take full advantage of PAT-ChIP approaches, procedures able to increase the purity and homogeneity of cell populations from FFPE tissues are required. Results In this study, we tested the use of both core needle biopsies (CNBs) and laser microdissection (LMD), evaluating the compatibility of these methods with the PAT-ChIP procedure. Modifications of the original protocols were introduced in order to increase reproducibility and reduce experimental time. We first demonstrated that chromatin can be prepared and effectively immunoprecipitated starting from 0.6-mm-diameter CNBs. Subsequently, in order to assess the applicability of PAT-ChIP to LMD samples, we tested the effects of hematoxylin or eosin staining on chromatin extraction and immunoprecipitation, as well as the reproducibility of our technique when using particularly low quantities of starting material. Finally, we carried out the PAT-ChIP using chromatin extracted from either normal tissue or neoplastic lesions, the latter obtained by LMD from FFPE lung sections derived from mutant K-rasv12 transgenic mice or from human adeno- or squamous lung carcinoma samples. Well characterized histone post-translational modifications (HPTMs), such as H3K4me3, H3K27me3, H3K27Ac, and H3K9me3, were specifically immunoselected, as well as the CTCF transcription factor and RNA polymerase II (Pol II). Conclusions Epigenetic profiling can be performed on enriched cell populations obtained from FFPE tissue sections. The improved PAT-ChIP protocol will be used for the discovery and/or validation of novel epigenetic biomarkers in FFPE human samples.
    Epigenetics & Chromatin 08/2014; 7(1):18. DOI:10.1186/1756-8935-7-18 · 5.33 Impact Factor
  • Source
    • "Mir-485 can inhibit breast cancer migration, in addition to inhibition of colony formation in vitro [76]. Mir-296 inhibits Scrib, a regulator of cell motility, thus inhibiting growth in vivo, and repression of this micro-RNA increases tumor invasiveness in vitro [77]. Invasion and adhesion to extracellular matrix is an essential mechanism for metastasis development, and inhibition of this step may result in the low total metastatic burden observed in oligometastases by preventing colonization of distant organs by circulating tumor cells (Fig. 5). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oligometastasis is a cancer disease state characterized by a limited number of metastatic tumors involving single or few organs and with biological properties that make them potentially amenable to locoregional antitumor therapy. Current clinical data show that they are potentially curable with surgical resection or/and radiotherapy. Yet, mechanisms of progression from primary tumor to oligometastasis, rather than to polymetastases, is lacking in detail. In the current review we focus on the role of micro-RNAs in the regulation of metastases development and the role they may play in the differentiation of oligometastatic from polymetastatic progression. We also discuss the analyses of metastatic samples from oligo-and polymetastatic patients, which suggest that oligometastasis is a distinct biologic entity regulated in part by micro-RNAs. In addition, a review of the known functions of oligometastatic-specific micro-RNAs suggest that they regulate multiple steps in the metastatic cascade, including epithelial-mesenchymal transition, tumor invasion, intravasation, distant vascular extravasation and proliferation in a distant organ. Understanding the role of micro-RNAs and their target genes in oligometastatic disease may allow for the development of targeted therapies to effectively conrol the spread of metastases.
    Clinical and Experimental Metastasis 06/2014; 31(6). DOI:10.1007/s10585-014-9664-3 · 3.49 Impact Factor
Show more